Parkin (protein) - Knowledge

2534:), is an alpha-synuclein interacting protein that is enriched in the core of Lewy bodies and ubiquitinated by parkin in a manner abolished by familial PD-associated mutations. Parkin might promote aggregation of alpha-synuclein and synphilin-1 into Lewy bodies, which are conjugated to Lys63-linked poly-Ub chains and directed towards autophagic degradation. Parkin mutations therefore inhibit this mechanism, leading to toxic accumulation of soluble proteins that overloads the proteasome. Protein aggregation triggers neuronal toxicity, whilst accounting for lack of ubiquitinated Lewy bodies in parkin-mutant PD. Similarly, native parkin reduces death of SH-SY5Y neurons by ubiquitinating other Lewy body constituents, such as the 347: 324: 221: 246: 598: 6018: 353: 252: 46: 6033: 6671: 1979: 5733:"Chromosome 6-linked autosomal recessive early-onset Parkinsonism: linkage in European and Algerian families, extension of the clinical spectrum, and evidence of a small homozygous deletion in one family. The French Parkinson's Disease Genetics Study Group, and the European Consortium on Genetic Susceptibility in Parkinson's Disease" 2500:

In accordance with its critical role in mitochondrial quality control, more than 120 pathogenic, PD-inducing mutations have been characterised on parkin. Such mutations may be hereditary or stochastic and are associated with structural instability, reduced catalytic efficiency and aberrant substrate

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Lücking CB, Abbas N, Dürr A, Bonifati V, Bonnet AM, de Broucker T, De Michele G, Wood NW, Agid Y, Brice A (October 1998). "Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in

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Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destée A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A (August 2003). "How much phenotypic variation can be

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blocked by RING0, while the E2 binding domain on RING1 is occluded by Ubl and REP. Activating stimuli disrupt these interdomain interactions and induce parkin to collapse along the RING1-RING0 interface. The active site of RING2 is drawn towards E2-Ub bound to RING1, facilitating formation of the

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cells significantly reduced parkin recruitment to depolarised mitochondria and their subsequent clearance, highlighting the critical role of VDAC1 as a selective marker of mitochondrial damage and instigator of mitophagy. Following Ub conjugation, parkin recruits autophagy receptors such as p62,

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Cartoon representation of parkin in its autoinhibited state, with the catalytic cysteine in RING2 occluded by RING0 while Ubl and REP linker prevents E2 from binding to RING1. RING0, RING1, IBR and RING2 each coordinate two Zn ions (approximate location denoted by grey circles) for structural

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neurons are particularly reliant on their proper function for clearance of reactive oxygen species produced by dopamine metabolism, and to supply high energy requirements of catecholamine synthesis. Their susceptibility to oxidative damage and metabolic stress render catecholaminergic neurons

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residues Lys161, Arg163 and Lys211 that forms a putative phosphate binding site. Considering that RING0 is unique to parkin and that its hydrophobic interface with RING1 buries Cys431 in inactive parkin, targeting of phosphorylated Ub and/or Ubl towards this binding niche might be critical in

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and phosphorylated by PINK1, which simultaneously phosphorylates Ub pre-conjugated to mitochondrial membrane proteins. PINK1 and Ub phosphorylation facilitate parkin activation and further assembly of mono- and poly-Ub chains. Considering the proximity of these chains to PINK1, further

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Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizu N, Mizuno Y (May 1999). "Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients".

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Abbas N, Lücking CB, Ricard S, Dürr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Böhme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A (April 1999).

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Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schäffer AA, Yamamura Y, Nakamura S, Kuzuhara S, Tsuji S, Mizuno Y (March 1997).

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Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (May 2006). "High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease".

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Fukae J, Sato S, Shiba K, Sato K, Mori H, Sharp PA, Mizuno Y, Hattori N (February 2009). "Programmed cell death-2 isoform1 is ubiquitinated by parkin and increased in the substantia nigra of patients with autosomal recessive Parkinson's disease".

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Müller-Rischart AK, Pilsl A, Beaudette P, Patra M, Hadian K, Funke M, Peis R, Deinlein A, Schweimer C, Kuhn PH, Lichtenthaler SF, Motori E, Hrelia S, Wurst W, Trümbach D, Langer T, Krappmann D, Dittmar G, Tatzelt J, Winklhofer KF (March 2013).

5845:"A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease" 5774:

Hattori N, Matsumine H, Asakawa S, Kitada T, Yoshino H, Elibol B, Brookes AJ, Yamamura Y, Kobayashi T, Wang M, Yoritaka A, Minoshima S, Shimizu N, Mizuno Y (August 1998). "Point mutations (Thr240Arg and Gln311Stop) in the Parkin gene".

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binding and ubiquitination. Mutations can generally be categorised into three groups, depending on their location. Firstly, those clustered around Zn-coordinating residues on RING and IBR might compromise structural integrity and impair

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before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.

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Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (October 2001). "Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease".

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Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N (June 2014). "Ubiquitin is phosphorylated by PINK1 to activate parkin".

2573:, mediated by suppression of neuronal p53 expression and its downstream activation of the apoptotic cascade. Several PD-associated parkin mutations are localised to RING1 and might impair its ability to bind and downregulate the 4607:

Letessier A, Garrido-Urbani S, Ginestier C, Fournier G, Esterni B, Monville F, Adélaïde J, Geneix J, Xerri L, Dubreuil P, Viens P, Charafe-Jauffret E, Jacquemier J, Birnbaum D, Lopez M, Chaffanet M (January 2007).

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Choi P, Snyder H, Petrucelli L, Theisler C, Chong M, Zhang Y, Lim K, Chung KK, Kehoe K, D'Adamio L, Lee JM, Cochran E, Bowser R, Dawson TM, Wolozin B (October 2003). "SEPT5_v2 is a parkin-binding protein".

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Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (July 2000). "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase".

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Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L, Shaler T, Walker D, Yang Y, Regnstrom K, Diep L, Zhang Z, Chiou S, Bova M, Artis DR, Yao N, Baker J, Yednock T, Johnston JA (2013).

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Tassin J, Dürr A, de Broucker T, Abbas N, Bonifati V, De Michele G, Bonnet AM, Broussolle E, Pollak P, Vidailhet M, De Mari M, Marconi R, Medjbeur S, Filla A, Meco G, Agid Y, Brice A (July 1998).

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mutations. Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).

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Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism".

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Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism".

2189:, reinforcing the importance of parkin in segregating defective mitochondria from their functioning counterparts and limiting the spatial spread of mitochondrial dysfunction, prior to autophagy. 2505:. A second class of mutations, including Thr240Arg, affect residues in and around the E2 binding site and alter autoinhibition of RING1 by REP. Finally, Cys431Phe and Gly430Asp mutations impair 2066:

were found to ablate Ub-parkin binding whilst inhibiting parkin recruitment to damaged mitochondria. PINK1 also phosphorylates Ub at Ser65, accelerating its discharge from E2 and enhancing its

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Hattori N, Machida Y, Sato S, Noda K, Iijima-Kitami M, Kubo S, Mizuno Y (2006). "Molecular mechanisms of nigral neurodegeneration in Park2 and regulation of parkin protein by other proteins".

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Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (April 1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)".

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Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (April 1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)".

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Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (January 2008).

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associated with aberrant regulation of mitochondrial activity, as is postulated to occur in both inherited and idiopathic PD. For example, enhanced oxidative stress in neurons,

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The discovery of numerous non-mitochondrial parkin substrates reinforces the importance parkin in neuronal homeostasis, beyond its role in mitochondrial regulation. Potent

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Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W (February 2010). "PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1".

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and prevent the corruption of healthy mitochondria. Parkin is therefore required before mitophagy as it ubiquinates Mfn1/2, labelling it for proteasomal degradation.

2721: 2616:, suggesting that parkin deficiencies increase susceptibility to tumour-promoting events, rather than initiating tumour formation. Similarly, chromosomal breaks in 4989:

Corti O, Hampe C, Koutnikova H, Darios F, Jacquier S, Prigent A, Robinson JC, Pradier L, Ruberg M, Mirande M, Hirsch E, Rooney T, Fournier A, Brice A (June 2003).

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Corti O, Hampe C, Koutnikova H, Darios F, Jacquier S, Prigent A, Robinson JC, Pradier L, Ruberg M, Mirande M, Hirsch E, Rooney T, Fournier A, Brice A (June 2003).

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Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB,

2387:. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age. In humans, 1917:

known as autosomal recessive juvenile Parkinson's disease (AR-JP). Moreover, parkin is described to be necessary for mitophagy (autophagy of mitochondria).

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da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A, Safe S, Abou-Sleiman PM, Wood NW, Takahashi H, Goldberg MS, Shen J, Checler F (November 2009).

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The precise function of parkin is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the

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Sunada Y, Saito F, Matsumura K, Shimizu T (October 1998). "Differential expression of the parkin gene in the human brain and peripheral leukocytes".

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Consistent with parkin's potent anti-tumourigenic abilities, negative mutations and deletions have been reported in various tumours. For example,

4393:"Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases" 3170:

Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY, Ménade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K (June 2013).

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Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (June 2006). "p53 regulates mitochondrial respiration".

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through addition of Lys48-linked poly-Ub chains and directing them towards proteasomal degradation. Parkin also influences axonal transport and

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signalling, parkin enhances survival and protects cells from stress-induced apoptosis. Upon cellular insult, parkin activates the catalytic HOIP

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Tan JM, Wong ES, Kirkpatrick DS, Pletnikova O, Ko HS, Tay SP, Ho MW, Troncoso J, Gygi SP, Lee MK, Dawson VL, Dawson TM, Lim KL (February 2008).

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Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, Arends MJ (August 2010).

2820: 6691: 2372:) due to a mutation in the parkin protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset 2010:

residue (Cys431) that cleaves Ub off E2 and transiently binds it to E3 via a thioester bond. Ub transfer is aided by neighbouring residues

3975:"Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease" 346: 4801:"Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain" 2662:

development in mouse models. Parkin is therefore a potent modulator of tumour progression, without directly instigating tumourigenesis.

2376:. In one study of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% 1750: 6066: 2261:

than other LUBAC-associated factors HOIL-1 and sharpin, meaning that parkin mobilisation significantly enhances tolerance to moderate

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Under resting conditions, the tightly coiled conformation of parkin renders it inactive, as access to the catalytic RING2 residue is

1757: 323: 6390: 4991:"The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration" 4434:"The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration" 2612:

at 6q25-q27 locus. Parkin deficiency further diminished disease-free survival in infrared-irradiated mice without increasing tumour

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were demonstrated in cell cultures over-expressing parkin, although the existence of such mechanisms at physiological parkin levels

3879:"[Use of balneo-, peloid- and centimeter-wave therapy in the complex treatment of patients with circumscribed scleroderma]" 2306:

promoter via its RING1 domain. Conversely, parkin may be a transcriptional target of p53 in H460 lung cells, where it mediates the

4209:"Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled" 6345: 4901:"CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity" 4164:

Ishikawa A, Takahashi H (November 1998). "Clinical and neuropathological aspects of autosomal recessive juvenile parkinsonism".

2671: 6350: 2807: 2786: 1862: 4610:"Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer" 2196:, a voltage-gated anion channel that undergoes a conformational change upon mitochondrial membrane depolarisation, exposing a 6340: 6234: 4760:"alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease" 2442: 1850: 6546: 6357: 6183: 5929: 5163:"The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI" 4845:"Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity" 2803: 1877:

and proteasomal mechanisms. Parkin also enhances cell survival by suppressing both mitochondria-dependent and -independent

245: 220: 69: 6059: 4942:"An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin" 2782: 2143:. However, upon mitochondrial damage, degradation of fusion proteins is necessary to separate them from the network via 1935:

is that parkin helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of parkin include

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Fishman PS, Oyler GA (July 2002). "Significance of the parkin gene and protein in understanding Parkinson's disease".

4651:"PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice" 1906: 6203: 6178: 6163: 6123: 2123:

and causes it to aggregate on the outer mitochondrial membrane (OMM). Parkin is recruited to mitochondria following

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Iguchi M, Kujuro Y, Okatsu K, Koyano F, Kosako H, Kimura M, Suzuki N, Uchiyama S, Tanaka K, Matsuda N (July 2013).

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cycle involving synergistic action of parkin and PINK1. Following severe cellular insult, rundown of mitochondrial

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promoter, leading to enhanced p53 expression. Parkin-mutant PD patients also exhibit a four-fold elevation in p53

6647: 6634: 6621: 6608: 6595: 6582: 6569: 6315: 6254: 6225: 6108: 6099: 5990: 4560:"Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies" 2539: 2323: 2140: 352: 251: 6541: 6208: 6133: 6118: 6495: 6438: 6090: 5969: 2490: 2059: 2027: 1571: 170: 6188: 6168: 6153: 6113: 5249:

Saito M, Matsumine H, Tanaka H, Ishikawa A, Matsubayashi S, Hattori Y, Mizuno Y, Tsuji S (January 1997). "".

5122:"Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase" 4758:

Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H, Rockenstein E, Imam SZ, Masliah E (March 2008).

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phosphorylation of Ub at Ser65 is likely, potentiating parkin mobilisation and substrate ubiquitination in a

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between Ubl and neighbouring subregions, reducing autoinhibitory effects of this N-terminus domain. Ser65Ala

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studies identified additional OMM proteins as parkin substrates, including fission protein FIS, its adaptor

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Yu F, Zhou J (July 2008). "Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress".

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recognition, a unique RING0 domain and a repressor (REP) region that tonically suppresses ligase activity.

6305: 2402: 2129: 1914: 1886: 5624:"Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27" 6464: 6383: 6335: 5960: 2144: 1082:

negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway

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Poorkaj P, Nutt JG, James D, Gancher S, Bird TD, Steinbart E, Schellenberg GD, Payami H (August 2004).

1967:. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins 6263: 5983: 5666: 4662: 4031: 3788: 3679: 3570: 3304: 3245: 3183: 3124: 2865: 2494: 2454: 2315: 2120: 234: 4075:"parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease" 3929:"The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO" 149: 6500: 2418: 2295: 2258: 1819: 1816: 1729: 1674: 3113:"Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect" 2581:, insinuating that failure of parkin-mediated anti-apoptosis might be involved in etiology of PD. 6433: 5941: 5903: 5830: 5690: 5601: 5425: 5353: 5295: 5227: 5066: 4971: 4874: 4737: 4373: 4326: 4282: 4189: 4146: 4102: 4055: 3859: 3328: 3209: 2889: 2116: 1999: 1182:

negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

194: 1733: 1708: 1704: 1700: 1670: 1649: 1645: 1641: 3234:"Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases" 5933: 5895: 5866: 5822: 5792: 5762: 5719: 5682: 5645: 5589: 5579: 5554: 5511: 5468: 5417: 5384: 5345: 5316: 5287: 5258: 5219: 5184: 5143: 5102: 5058: 5012: 4963: 4922: 4866: 4822: 4781: 4729: 4690: 4631: 4589: 4555: 4532: 4496: 4455: 4414: 4365: 4318: 4274: 4238: 4181: 4138: 4094: 4047: 4004: 3950: 3908: 3851: 3816: 3757: 3705: 3645: 3596: 3539: 3485: 3431: 3382: 3320: 3271: 3201: 3152: 3086: 3025: 2965: 2924: 2881: 2655: 2644: 2469: 2406: 2373: 2365:) is the parkin gene that may cause a form of autosomal recessive juvenile Parkinson disease ( 2307: 2112: 2067: 2063: 597: 142: 62: 6051: 5120:

Liu M, Aneja R, Sun X, Xie S, Wang H, Wu X, Dong JT, Li M, Joshi HC, Zhou J (December 2008).

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Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW (April 2013).

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that promote mitochondria fusion into dynamic, tubular complexes that maximise efficiency of

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Like other members of the RING-between-RING (RBR) family of E3 ligases, parkin possesses two

6479: 6474: 6448: 6376: 6268: 5925: 5887: 5856: 5814: 5784: 5752: 5744: 5711: 5674: 5635: 5571: 5544: 5536: 5501: 5493: 5458: 5450: 5409: 5374: 5337: 5279: 5211: 5174: 5133: 5094: 5048: 5040: 5002: 4953: 4912: 4856: 4812: 4771: 4721: 4709: 4680: 4670: 4621: 4579: 4571: 4524: 4486: 4445: 4404: 4357: 4310: 4266: 4228: 4220: 4173: 4130: 4086: 4039: 3994: 3986: 3940: 3898: 3890: 3843: 3806: 3796: 3747: 3739: 3695: 3687: 3668:"Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization" 3635: 3627: 3616:"Fission and selective fusion govern mitochondrial segregation and elimination by autophagy" 3586: 3578: 3529: 3521: 3475: 3465: 3421: 3413: 3372: 3362: 3312: 3261: 3253: 3191: 3142: 3132: 3076: 3068: 3015: 3007: 2955: 2916: 2873: 2651: 2624: 2578: 2398: 2388: 2331: 2272: 2175: 1956: 1921: 1854: 1427:

negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway

439: 370: 314: 269: 4475:"Identification of far upstream element-binding protein-1 as an authentic Parkin substrate" 3351:"Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation" 6696: 6526: 6510: 6423: 5965: 5613: 4899:

Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R (July 2002).

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Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A (March 2003).

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Choi P, Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee JM,

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abilities of parkin in attenuating dopaminergic neurotoxicity, mitochondrial swelling and

2517: 2478: 2465: 2434: 2410: 2226: 2074: 2039: 2019: 414: 190: 5398:"Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease" 5670: 4666: 4035: 3792: 3683: 3574: 3308: 3249: 3187: 3128: 2869: 6675: 6564: 6505: 6310: 5757: 5732: 5640: 5623: 5549: 5524: 5463: 5438: 4685: 4650: 4584: 4559: 4233: 4208: 3999: 3974: 3903: 3878: 3811: 3776: 3752: 3727: 3700: 3667: 3640: 3615: 3591: 3558: 3534: 3509: 3480: 3453: 3426: 3401: 3377: 3350: 3266: 3233: 3147: 3112: 3081: 3056: 3020: 2995: 2613: 2547: 2521: 2510: 2276: 2163: 2124: 2108: 2006:

forms the binding site for E2 Ub-conjugating enzyme while RING2 contains the catalytic

1928: 1894: 1834: 45: 5891: 5818: 5506: 5481: 5098: 4958: 4941: 4917: 4900: 4861: 4844: 1441: 1436: 1431: 1426: 1421: 1416: 1411: 1406: 1401: 1396: 1391: 1386: 1381: 1376: 1371: 1366: 1361: 1356: 1351: 1346: 1341: 1336: 1331: 1326: 1321: 1316: 1311: 1306: 1301: 1296: 1291: 1286: 1281: 1276: 1271: 1266: 1261: 1256: 1251: 1246: 1241: 1236: 1231: 1226: 1221: 1216: 1211: 1206: 1201: 1196: 1191: 1186: 1181: 1176: 1171: 1166: 1161: 1156: 1151: 1146: 1141: 1136: 1131: 1126: 1121: 1116: 1111: 1106: 1101: 1096: 1091: 1086: 1081: 1076: 1071: 1066: 1061: 1056: 1051: 1046: 1041: 1036: 1031: 1026: 1021: 1016: 1011: 1006: 1001: 996: 991: 986: 981: 976: 971: 966: 961: 956: 951: 946: 941: 936: 931: 926: 921: 916: 911: 906: 890: 885: 880: 875: 870: 865: 860: 855: 850: 845: 840: 835: 830: 825: 820: 815: 810: 805: 789: 784: 779: 774: 769: 764: 759: 754: 749: 744: 739: 734: 729: 724: 719: 714: 709: 704: 699: 694: 689: 684: 679: 674: 669: 664: 659: 654: 649: 644: 639: 6685: 6469: 6428: 4725: 3213: 3052: 2628: 2474: 2430: 2426: 2422: 2280: 1991: 1948: 626: 5945: 5907: 5834: 5429: 5357: 5299: 4878: 4741: 4377: 4286: 4193: 4106: 4059: 3863: 1367:

parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization

174: 6418: 5694: 5231: 5070: 4551: 4330: 4224: 4150: 3777:"Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility" 3728:"Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism" 3332: 2893: 2605: 2597: 2566: 2458: 2438: 2288: 2250: 1870: 432: 211: 5044: 4975: 3510:"The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications" 1007:

negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator

5575: 5540: 5215: 3945: 3928: 2960: 2943: 198: 6642: 6577: 6413: 3743: 2843:

National Center for Biotechnology Information, U.S. National Library of Medicine

2825:

National Center for Biotechnology Information, U.S. National Library of Medicine

2757: 2601: 2593: 2414: 2339: 2327: 2319: 2311: 2242: 2183: 2156: 1861:

bond and mobilises it in an ATP-dependent process. Ub is then transferred to an

1842: 1372:

positive regulation of proteasomal ubiquitin-dependent protein catabolic process

6670: 4655:

Proceedings of the National Academy of Sciences of the United States of America

3781:

Proceedings of the National Academy of Sciences of the United States of America

3117:

Proceedings of the National Academy of Sciences of the United States of America

515: 5805:

Parkinson's Disease and the French Parkinson's Disease Genetics Study Group".

5341: 5283: 3454:"Will Crystal Parkin Help in Understanding the Future of Parkinson's Disease?" 2636: 2632: 2446: 2377: 2335: 2213:, facilitating assembly of autophagosomes that digest defective mitochondria. 2023: 1964: 1960: 1932: 1910: 1890: 1813: 331: 228: 178: 5570:. Journal of Neural Transmission. Supplementa. Vol. 70. pp. 205–8. 5454: 5413: 3631: 3470: 6616: 6590: 5497: 4675: 4043: 3801: 3582: 3367: 3196: 3171: 3137: 2640: 2502: 2486: 2482: 2384: 2262: 2197: 2148: 2100: 2055: 2022:, whose assembly is required for parkin activation. Parkin also contains an 2015: 2011: 1885:

are associated with mitochondrial dysfunction, leading to neuronal death in

1882: 1878: 1874: 1873:

upon cellular insult and mediates the clearance of damaged mitochondria via

1858: 1849:. Ubiquitination involves the sequential action of three enzymes. First, an 1846: 1838: 1471: 932:

positive regulation of mitophagy in response to mitochondrial depolarization

575: 453: 398: 385: 297: 284: 186: 5937: 5899: 5870: 5788: 5715: 5593: 5558: 5515: 5472: 5421: 5388: 5349: 5320: 5291: 5223: 5188: 5147: 5138: 5121: 5106: 5062: 5016: 4967: 4926: 4870: 4826: 4817: 4800: 4785: 4776: 4759: 4733: 4694: 4635: 4626: 4609: 4593: 4528: 4500: 4491: 4474: 4459: 4418: 4369: 4322: 4278: 4242: 4142: 4098: 4051: 4008: 3954: 3912: 3855: 3820: 3761: 3709: 3649: 3600: 3543: 3525: 3489: 3435: 3417: 3386: 3324: 3275: 3205: 3156: 3090: 3029: 2969: 2920: 5961:

GeneReviews/NCBI/NIH/UW entry on Parkin Type of Juvenile Parkinson Disease

5861: 5844: 5826: 5796: 5766: 5723: 5686: 5649: 5262: 4536: 4185: 3894: 3775:

Shlevkov E, Kramer T, Schapansky J, LaVoie MJ, Schwarz TL (October 2016).

2928: 2885: 2162:

and TOMM70 that facilitate movement of proteins such as PINK1 across OMM.

1797: 1792: 153:, parkin RBR E3 ubiquitin protein ligase, AR-JP, LPRS2, PDJ, PARK2, Parkin 5379: 5366: 5179: 5162: 5007: 4990: 4450: 4433: 4409: 4392: 4090: 2230: 2222: 2210: 2082: 2018:

Glu444, which is involved in autoubiquitination. Together these form the

2007: 1985:

Schematic diagram delineating arrangement of parkin functional domains.

1940: 1925: 1781: 1616: 1597: 5328:

West AB, Maidment NT (March 2004). "Genetics of parkin-linked disease".

5053: 4361: 3691: 3316: 3172:"Structure of parkin reveals mechanisms for ubiquitin ligase activation" 2397:

gene have been implicated in 50% of inherited and 15% of juvenile-onset

785:

DNA-binding transcription repressor activity, RNA polymerase II-specific

4940:

Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R (June 2001).

4177: 3402:"Structure of the human Parkin ligase domain in an autoinhibited state" 3257: 3011: 2659: 2559: 2551: 2528:

is yet unconfirmed. Another parkin substrate, synphilin-1 (encoded by

2299: 2254: 2246: 2206: 2186: 2152: 1823: 1583: 1538: 947:

positive regulation of tumor necrosis factor-mediated signaling pathway

4134: 3111:

Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z (2011).

3072: 1978: 119: 115: 111: 107: 103: 99: 95: 91: 6629: 6399: 6273: 6086: 6082: 4799:

Fallon L, Moreau F, Croft BG, Labib N, Gu WJ, Fon EA (January 2002).

2739: 2709: 2621: 2570: 2530: 2506: 2450: 2257:-mediated apoptosis. Importantly, parkin activates HOIP with greater 2159: 2136: 2078: 2073:

Although structural changes following phosphorylation are uncertain,

2043: 2034: 1936: 1765: 1493: 5397: 4074: 3990: 3847: 2135:

Parkin substrates include mitofusins Mfn1 and Mfn2, which are large

17: 5930:

10.1002/1531-8249(199905)45:5<668::AID-ANA19>3.0.CO;2-Z

5748: 4575: 4270: 1869:

In particular, parkin recognises proteins on the outer membrane of

6603: 6283: 5678: 4712:(September 2001). "Co-association of parkin and alpha-synuclein". 4314: 2877: 2751: 2745: 2733: 2727: 2715: 2703: 2697: 2555: 2393: 2193: 2179: 2171: 2167: 2051: 2003: 1977: 1972: 1952: 1944: 3057:"The role of parkin in familial and sporadic Parkinson's disease" 1456: 1452: 1047:

proteasome-mediated ubiquitin-dependent protein catabolic process

6298: 6288: 2691: 2685: 2366: 2359: 2238: 2229:

of another E3 ligase LUBAC. HOIP triggers assembly of linear Ub

2201: 1968: 1830: 1347:

negative regulation of reactive oxygen species metabolic process

1212:

negative regulation of release of cytochrome c from mitochondria

166: 6372: 6055: 5979: 2086:

dismantling autoinhibitory complexes during parkin activation.

2014:

His433, which accepts a proton from Cys431 to activate it, and

1913:. Mutations in this gene are known to cause a familial form of 606: 5975: 2334:, characterising it as a critical tumour suppressor with anti- 2284: 2269: 1407:

positive regulation of retrograde transport, endosome to Golgi

6026:: Solution structure of ubiquitin-like domain of human parkin 2948:

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

2429:

for sporadic PD. Parkin-mutant PD could also involve loss of

2421:

PD due to parkin mutations is often early onset and lack the

1837:– the process whereby molecules are covalently labelled with 1012:

negative regulation of spontaneous neurotransmitter secretion

4473:

Ko HS, Kim SW, Sriram SR, Dawson VL, Dawson TM (June 2006).

2200:

domain for ubiquitination. Silencing of VDAC1 expression in

1282:

positive regulation of proteasomal protein catabolic process

2464:

While mitochondria are essential for ATP generation in any

6368: 5439:"How does parkin ligate ubiquitin to Parkinson's disease?" 2107:. Mitophagy is the elimination of damaged mitochondria in 1337:

positive regulation of I-kappaB kinase/NF-kappaB signaling

1137:

negative regulation of oxidative stress-induced cell death

2326:

during tumourigenesis. Parkin further elevates cytosolic

1352:

positive regulation of transcription by RNA polymerase II

1232:

negative regulation of transcription by RNA polymerase II

5161:

Huynh DP, Scoles DR, Nguyen D, Pulst SM (October 2003).

2077:

of parkin revealed a cationic pocket in RING0 formed by

1247:

positive regulation of protein linear polyubiquitination

422: 1417:

positive regulation of protein localization to membrane

1237:

regulation of reactive oxygen species metabolic process

1017:

negative regulation by host of viral genome replication

5309:

Seikagaku. The Journal of Japanese Biochemical Society

2405:(PD). While PD is traditionally regarded a late-onset 2038:

Ub-thioester intermediate. Parkin activation requires

1032:

negative regulation of canonical Wnt signaling pathway

6659: 5525:"Protein-protein interactions in the mammalian brain" 4207:

Keeney PM, Xie J, Capaldi RA, Bennett JP (May 2006).

2650:

expression, either due to reduced copy number or DNA

2493:

were reported in PD patients, while deletions in the

2310:

action of p53. Considering its role in mitochondrial

1412:

negative regulation of intralumenal vesicle formation

1302:

negative regulation of actin filament bundle assembly

1187:

negative regulation of primary amine oxidase activity

587: 5396:

Baptista MJ, Cookson MR, Miller DW (February 2004).

5367:"Parkin genetics: one model for Parkinson's disease" 4558:, Mellinghoff IK, Solit DB, Chan TA (January 2010). 6555: 6519: 6488: 6457: 6406: 6253: 6224: 6098: 5777:

Biochemical and Biophysical Research Communications

5251:

Nihon Rinsho. Japanese Journal of Clinical Medicine

4517:

Biochemical and Biophysical Research Communications

2565:Finally, parkin protects dopaminergic neurons from 2383:Patients with parkin mutations (PARK2) do not have 2302:neurons revealed that parkin directly binds to the 1722: 1693: 1663: 1634: 1397:

regulation of cellular response to oxidative stress

2799: 2797: 2795: 2778: 2776: 2774: 2233:on NF-κB essential modulator (NEMO), potentiating 3447: 3445: 2445:(SNpc). However, its symptoms resembles those of 1931:death in this disease is unclear. The prevailing 1432:positive regulation of autophagy of mitochondrion 1257:dopamine uptake involved in synaptic transmission 369: 268: 3726:Narendra D, Walker JE, Youle R (November 2012). 3721: 3719: 1267:regulation of protein targeting to mitochondrion 937:positive regulation of protein catabolic process 4894: 4892: 4890: 4888: 4838: 4836: 4753: 4751: 4342: 4340: 3968: 3966: 3964: 2722:Multisynthetase complex auxiliary component p38 2558:) respectively, giving it a modulatory role in 2314:, parkin aids p53 in maintaining mitochondrial 907:negative regulation of neuron apoptotic process 5365:Mata IF, Lockhart PJ, Farrer MJ (April 2004). 3661: 3659: 3503: 3501: 3499: 3344: 3342: 3289: 3287: 3285: 2989: 2987: 2985: 2983: 2981: 2979: 2944:"Ubiquitin: structures, functions, mechanisms" 2804:GRCm38: Ensembl release 89: ENSMUSG00000023826 2658:where it accelerated all stages of intestinal 1312:regulation of mitochondrial membrane potential 1177:negative regulation of protein phosphorylation 992:positive regulation of neurotransmitter uptake 6384: 6067: 5991: 3227: 3225: 3223: 3106: 3104: 3102: 3100: 3047: 3045: 3043: 3041: 3039: 1437:ubiquitin-dependent protein catabolic process 1207:regulation of canonical Wnt signaling pathway 8: 4079:American Journal of Medical Genetics. Part A 2994:Seirafi M, Kozlov G, Gehring K (June 2015). 1909:that mediates the targeting of proteins for 967:modulation of chemical synaptic transmission 927:positive regulation of mitochondrial fission 3559:"Mitochondrial fission, fusion, and stress" 2783:GRCh38: Ensembl release 89: ENSG00000185345 2279:reduction in transcription and activity of 1277:negative regulation of glucokinase activity 1162:negative regulation of mitochondrial fusion 1142:positive regulation of mitochondrial fusion 730:transcription cis-regulatory region binding 6391: 6377: 6369: 6074: 6060: 6052: 5998: 5984: 5976: 5272:Current Neurology and Neuroscience Reports 3732:Cold Spring Harbor Perspectives in Biology 3557:Youle RJ, van der Bliek AM (August 2012). 2513:and significantly reduce parkin function. 2449:PD, with patients presenting with resting 1826:that in humans and mice is encoded by the 1467: 1067:regulation of transcription, DNA-templated 856:Parkin-FBXW7-Cul1 ubiquitin ligase complex 622: 410: 309: 206: 80: 5968:at the U.S. National Library of Medicine 5860: 5756: 5639: 5568:Parkinson's Disease and Related Disorders 5548: 5505: 5462: 5378: 5178: 5137: 5052: 5006: 4957: 4916: 4860: 4816: 4775: 4684: 4674: 4625: 4583: 4490: 4449: 4408: 4232: 3998: 3944: 3902: 3810: 3800: 3751: 3699: 3639: 3590: 3533: 3479: 3469: 3425: 3376: 3366: 3265: 3195: 3146: 3136: 3080: 3019: 2959: 2485:, corresponding with reduced activity of 2322:production, thus preventing onset of the 1841:(Ub) and directed towards degradation in 1402:negative regulation of exosomal secretion 1342:positive regulation of dendrite extension 645:DNA-binding transcription factor activity 5087:Brain Research. Molecular Brain Research 1307:regulation of dopamine metabolic process 1242:regulation of neurotransmitter secretion 1202:regulation of mitochondrion organization 1122:response to endoplasmic reticulum stress 972:regulation of synaptic vesicle transport 917:negative regulation of insulin secretion 6666: 6013: 2942:Pickart CM, Eddins MJ (November 2004). 2770: 2437:alongside the hallmark degeneration of 2298:with truncated versions of parkin into 997:regulation of glucose metabolic process 5609: 5599: 2654:, was further detected in spontaneous 2544:far upstream element-binding protein 1 2253:release from mitochondria, inhibiting 1387:positive regulation of protein binding 1332:positive regulation of gene expression 1112:negative regulation of gene expression 735:ubiquitin-protein transferase activity 35: 6139:D-alanine—poly(phosphoribitol) ligase 2002:and an in-between-RING (IBR) region. 1152:proteasomal protein catabolic process 1147:protein localization to mitochondrion 374: 335: 330: 273: 232: 227: 7: 962:cellular response to toxic substance 957:regulation of protein ubiquitination 942:synaptic transmission, glutamatergic 715:ubiquitin conjugating enzyme binding 5480:Pankratz N, Foroud T (April 2004). 5126:The Journal of Biological Chemistry 4805:The Journal of Biological Chemistry 4764:The Journal of Biological Chemistry 4479:The Journal of Biological Chemistry 3355:The Journal of Biological Chemistry 1959:). Additionally, parkin contains a 1392:mitochondrion to lysosome transport 1172:negative regulation of neuron death 1062:free ubiquitin chain polymerization 987:synaptic transmission, dopaminergic 760:ubiquitin-specific protease binding 6279:Von Hippel–Lindau tumor suppressor 5737:American Journal of Human Genetics 5628:American Journal of Human Genetics 3883:Vestnik Dermatologii I Venerologii 2670:Parkin (ligase) has been shown to 2318:while limiting glucose uptake and 2119:prevents import of PINK1 into the 2026:Ub-like domain (Ubl) for specific 1833:. Parkin plays a critical role in 1719: 1690: 1660: 1631: 1607: 1588: 1562: 1543: 1517: 1498: 1322:negative regulation of JNK cascade 1157:cellular response to manganese ion 1132:central nervous system development 1022:positive regulation of DNA binding 790:protein-containing complex binding 765:G protein-coupled receptor binding 592: 510: 448: 427: 25: 5373:. 13 Spec No 1 (90001): R127-33. 4121:attributed to parkin genotype?". 3400:Wauer T, Komander D (July 2013). 2192:During mitophagy, parkin targets 2174:) is an OMM protein critical for 1287:protein K63-linked ubiquitination 1252:protein K48-linked ubiquitination 1127:protein K11-linked ubiquitination 1107:protein K27-linked ubiquitination 1097:negative regulation of cell death 912:protein K29-linked ubiquitination 780:ubiquitin protein ligase activity 6669: 6245:Long-chain-fatty-acid—CoA ligase 6031: 6016: 4726:10.1097/00001756-200109170-00017 2639:potential and worsening overall 1077:norepinephrine metabolic process 1052:regulation of dopamine secretion 1002:protein K6-linked ubiquitination 770:ubiquitin protein ligase binding 596: 358: 351: 345: 322: 257: 250: 244: 219: 44: 5482:"Genetics of Parkinson disease" 5437:Kahle PJ, Haass C (July 2004). 2996:"Parkin structure and function" 2099:Parkin plays a crucial role in 1924:of the parkin protein leads to 1863:E2 ubiquitin-conjugating enzyme 1442:regulation of apoptotic process 1382:regulation of protein stability 821:perinuclear region of cytoplasm 6341:Carbamoyl phosphate synthetase 6235:Succinyl coenzyme A synthetase 4225:10.1523/JNEUROSCI.0984-06.2006 3508:Durcan TM, Fon EA (May 2015). 3452:Olszewska DA, Lynch T (2015). 2443:substantia nigra pars compacta 1851:E1 ubiquitin-activating enzyme 607:More reference expression data 576:More reference expression data 1: 5892:10.1016/S0304-3940(98)00697-1 5819:10.1016/S0140-6736(05)60746-5 5307:Takahashi R (June 2002). "". 5099:10.1016/s0169-328x(03)00318-8 5045:10.1016/j.febslet.2008.12.055 4959:10.1016/s0092-8674(01)00407-x 4918:10.1016/s1097-2765(02)00583-x 4862:10.1016/s0896-6273(03)00084-9 1297:regulation of lipid transport 1292:cellular response to dopamine 881:mitochondrion-derived vesicle 665:cullin family protein binding 343: 242: 6041:: IBR domain of Human Parkin 5576:10.1007/978-3-211-45295-0_31 5541:10.1113/jphysiol.2006.115717 5216:10.1016/j.neulet.2008.05.052 3946:10.1016/j.molcel.2013.01.036 2961:10.1016/j.bbamcr.2004.09.019 2330:levels and protects against 1955:and parkin itself (see also 1117:transcription, DNA-templated 1102:response to oxidative stress 836:SCF ubiquitin ligase complex 6692:Genes on human chromosome 6 5523:Suzuki H (September 2006). 4213:The Journal of Neuroscience 3744:10.1101/cshperspect.a011338 2409:condition characterised by 1907:ubiquitin-proteasome system 952:neuron cellular homeostasis 655:histone deacetylase binding 6713: 6326:Holocarboxylase synthetase 6321:Argininosuccinate synthase 6294:Anaphase-promoting complex 2550:through ubiquitination of 1422:autophagy of mitochondrion 1327:dopamine metabolic process 1227:protein polyubiquitination 1222:mitochondrion organization 1167:protein autoubiquitination 982:protein monoubiquitination 891:protein-containing complex 675:heat shock protein binding 28: 6547:Michaelis–Menten kinetics 6358:Glutamate–cysteine ligase 6316:Adenylosuccinate synthase 6109:Aminoacyl tRNA synthetase 6011: 5529:The Journal of Physiology 5342:10.1007/s00439-003-1074-6 5284:10.1007/s11910-002-0004-7 2839:"Mouse PubMed Reference:" 2821:"Human PubMed Reference:" 2620:suppressed expression of 2540:aminoacyl-tRNA synthetase 2141:oxidative phosphorylation 1796: 1791: 1787: 1780: 1764: 1751:Chr 6: 161.35 – 162.73 Mb 1745: 1726: 1697: 1686: 1667: 1638: 1627: 1614: 1610: 1595: 1591: 1582: 1569: 1565: 1550: 1546: 1537: 1524: 1520: 1505: 1501: 1492: 1477: 1470: 1466: 1450: 1092:protein metabolic process 1087:adult locomotory behavior 1037:Unfolded Protein Response 750:identical protein binding 625: 621: 604: 595: 586: 573: 522: 513: 460: 451: 421: 413: 409: 392: 379: 342: 321: 312: 308: 291: 278: 241: 218: 209: 205: 160: 157: 147: 140: 135: 88: 83: 66: 61: 56: 52: 43: 38: 6439:Diffusion-limited enzyme 5970:Medical Subject Headings 5849:Human Molecular Genetics 5455:10.1038/sj.embor.7400188 5414:10.1177/1073858403260392 5371:Human Molecular Genetics 5167:Human Molecular Genetics 4995:Human Molecular Genetics 4438:Human Molecular Genetics 4397:Human Molecular Genetics 3877:Aleksaniants GD (2013). 3632:10.1038/sj.emboj.7601963 3471:10.3389/fneur.2015.00035 2497:were found in the SNpc. 2491:electron transport chain 2237:of mitochondrial GTPase 2111:, and is dependent on a 2060:hydrophobic interactions 2054:. Addition of a charged 1990:stability, leading to a 1853:binds to inactive Ub in 1758:Chr 17: 11.06 – 12.28 Mb 1377:protein deubiquitination 861:ubiquitin ligase complex 5498:10.1602/neurorx.1.2.235 4676:10.1073/pnas.1009941107 4044:10.1126/science.1126863 3802:10.1073/pnas.1612283113 3583:10.1126/science.1219855 3514:Genes & Development 3368:10.1074/jbc.M113.467530 3197:10.1126/science.1237908 3138:10.1073/pnas.1113884108 2350: 2105:reactive oxygen species 2048:serine/threonine kinase 1272:protein destabilization 1262:regulation of autophagy 31:Parkin (disambiguation) 6306:Glutathione synthetase 5789:10.1006/bbrc.1998.9134 5716:10.1006/geno.1997.5196 5139:10.1074/jbc.M806860200 4818:10.1074/jbc.M109806200 4777:10.1074/jbc.M710418200 4627:10.1038/sj.onc.1209772 4529:10.1006/bbrc.1998.9134 4492:10.1074/jbc.C600041200 3526:10.1101/gad.262758.115 3458:Frontiers in Neurology 3418:10.1038/emboj.2013.125 2921:10.1006/geno.1997.5196 2596:was reduced in 85% of 2569:induced by PD-mimetic 2554:and synaptotagmin XI ( 2249:structure and reduces 2221:Through activation of 2130:self-reinforcing cycle 1995: 1362:protein ubiquitination 720:protein kinase binding 6532:Eadie–Hofstee diagram 6465:Allosteric regulation 6336:Asparagine synthetase 6240:Acetyl—CoA synthetase 3895:10.1038/emboj.2013.70 3238:Nature Communications 2635:integrity, enhancing 2631:, thereby comprising 2604:were associated with 2346:Clinical significance 2145:mitochondrial fission 1981: 1943:, p38 tRNA synthase, 1217:protein stabilization 1197:mitochondrial fission 846:endoplasmic reticulum 685:Hsp70 protein binding 640:phospholipase binding 337:Chromosome 17 (mouse) 6542:Lineweaver–Burk plot 6264:Glutamine synthetase 5880:Neuroscience Letters 5204:Neuroscience Letters 4166:Journal of Neurology 4091:10.1002/ajmg.a.30157 3055:, Dawson VL (2014). 2495:mitochondrial genome 2455:postural instability 2391:mutations in parkin 2121:mitochondrial matrix 1057:zinc ion homeostasis 775:transferase activity 740:F-box domain binding 700:beta-catenin binding 484:gastrocnemius muscle 376:17 A1|17 7.8 cM 235:Chromosome 6 (human) 84:List of PDB id codes 57:Available structures 29:For other uses, see 5918:Annals of Neurology 5862:10.1093/hmg/8.4.567 5671:1998Natur.392..605K 4667:2010PNAS..10715145P 4362:10.1038/nm1001-1144 4172:(11 Suppl 3): 4–9. 4123:Annals of Neurology 4036:2006Sci...312.1650M 3979:Nature Cell Biology 3836:Nature Cell Biology 3793:2016PNAS..113E6097S 3787:(41): E6097–E6106. 3692:10.1038/nature12043 3684:2013Natur.496..372S 3575:2012Sci...337.1062Y 3317:10.1038/nature13392 3309:2014Natur.510..162K 3250:2013NatCo...4.1982R 3188:2013Sci...340.1451T 3129:2011PNAS..10816259Z 2870:1998Natur.392..605K 2419:autosomal recessive 2403:Parkinson's disease 2351:Parkinson's disease 2000:RING finger domains 1915:Parkinson's disease 1887:Parkinson's disease 1820:E3 ubiquitin ligase 1072:locomotory behavior 6501:Enzyme superfamily 6434:Enzyme promiscuity 5402:The Neuroscientist 5380:10.1093/hmg/ddh089 5180:10.1093/hmg/ddg269 5008:10.1093/hmg/ddg159 4451:10.1093/hmg/ddg159 4410:10.1093/hmg/ddm320 4178:10.1007/pl00007745 3258:10.1038/ncomms2982 3067:(Suppl 1): S32-9. 3061:Movement Disorders 3012:10.1111/febs.13249 2117:membrane potential 2064:missense mutations 1996: 1572:ENSMUSG00000023826 1042:aggresome assembly 900:Biological process 799:Cellular component 670:PDZ domain binding 650:SH3 domain binding 633:Molecular function 6657: 6656: 6366: 6365: 6257:: Carbon-Nitrogen 6049: 6048: 5585:978-3-211-28927-3 4135:10.1002/ana.10613 3073:10.1002/mds.22798 2656:colorectal cancer 2645:Haploinsufficient 2470:catecholaminergic 2425:protein deposits 2407:neurodegenerative 2374:Parkinson disease 2308:tumour suppressor 2268:Parkin possesses 2241:. Increased OPA1 2113:positive feedback 2103:and clearance of 1994:of 8 Zn2+/parkin. 1963:motif that binds 1807: 1806: 1803: 1802: 1776: 1775: 1741: 1740: 1716: 1715: 1682: 1681: 1657: 1656: 1623: 1622: 1604: 1603: 1578: 1577: 1559: 1558: 1533: 1532: 1514: 1513: 1462: 1461: 876:neuron projection 745:ubiquitin binding 725:chaperone binding 680:metal ion binding 617: 616: 613: 612: 582: 581: 569: 568: 507: 506: 492:prefrontal cortex 405: 404: 304: 303: 131: 130: 127: 126: 67:Ortholog search: 16:(Redirected from 6704: 6674: 6673: 6665: 6537:Hanes–Woolf plot 6480:Enzyme activator 6475:Enzyme inhibitor 6449:Enzyme catalysis 6393: 6386: 6379: 6370: 6269:Ubiquitin ligase 6076: 6069: 6062: 6053: 6035: 6020: 6000: 5993: 5986: 5977: 5949: 5911: 5874: 5864: 5838: 5813:(9137): 1355–6. 5800: 5770: 5760: 5727: 5698: 5653: 5643: 5617: 5611: 5607: 5605: 5597: 5562: 5552: 5519: 5509: 5476: 5466: 5433: 5392: 5382: 5361: 5324: 5303: 5266: 5236: 5235: 5199: 5193: 5192: 5182: 5158: 5152: 5151: 5141: 5117: 5111: 5110: 5081: 5075: 5074: 5056: 5027: 5021: 5020: 5010: 4986: 4980: 4979: 4961: 4937: 4931: 4930: 4920: 4896: 4883: 4882: 4864: 4840: 4831: 4830: 4820: 4796: 4790: 4789: 4779: 4755: 4746: 4745: 4705: 4699: 4698: 4688: 4678: 4661:(34): 15145–50. 4646: 4640: 4639: 4629: 4604: 4598: 4597: 4587: 4547: 4541: 4540: 4511: 4505: 4504: 4494: 4470: 4464: 4463: 4453: 4429: 4423: 4422: 4412: 4388: 4382: 4381: 4344: 4335: 4334: 4297: 4291: 4290: 4253: 4247: 4246: 4236: 4204: 4198: 4197: 4161: 4155: 4154: 4117: 4111: 4110: 4070: 4064: 4063: 4030:(5780): 1650–3. 4019: 4013: 4012: 4002: 3970: 3959: 3958: 3948: 3923: 3917: 3916: 3906: 3874: 3868: 3867: 3831: 3825: 3824: 3814: 3804: 3772: 3766: 3765: 3755: 3723: 3714: 3713: 3703: 3663: 3654: 3653: 3643: 3620:The EMBO Journal 3611: 3605: 3604: 3594: 3569:(6098): 1062–5. 3554: 3548: 3547: 3537: 3505: 3494: 3493: 3483: 3473: 3449: 3440: 3439: 3429: 3412:(15): 2099–112. 3406:The EMBO Journal 3397: 3391: 3390: 3380: 3370: 3361:(30): 22019–32. 3346: 3337: 3336: 3291: 3280: 3279: 3269: 3229: 3218: 3217: 3199: 3182:(6139): 1451–5. 3167: 3161: 3160: 3150: 3140: 3123:(39): 16259–64. 3108: 3095: 3094: 3084: 3049: 3034: 3033: 3023: 3000:The FEBS Journal 2991: 2974: 2973: 2963: 2939: 2933: 2932: 2904: 2898: 2897: 2853: 2847: 2846: 2835: 2829: 2828: 2817: 2811: 2801: 2790: 2780: 2652:hypermethylation 2625:scaffold protein 2579:immunoreactivity 2509:activity at the 2389:loss-of-function 2332:oxidative stress 2273:binding affinity 2176:axonal transport 2046:Ser65 in Ubl by 1957:ubiquitin ligase 1922:loss of function 1855:eukaryotic cells 1789: 1788: 1760: 1753: 1736: 1720: 1711: 1691: 1687:RefSeq (protein) 1677: 1661: 1652: 1632: 1608: 1589: 1563: 1544: 1518: 1499: 1468: 1192:startle response 705:zinc ion binding 623: 609: 600: 593: 578: 518: 516:Top expressed in 511: 456: 454:Top expressed in 449: 428: 411: 401: 388: 377: 362: 355: 349: 338: 326: 310: 300: 287: 276: 261: 254: 248: 237: 223: 207: 201: 199:PRKN - orthologs 152: 145: 122: 81: 75: 54: 53: 48: 36: 21: 6712: 6711: 6707: 6706: 6705: 6703: 6702: 6701: 6682: 6681: 6680: 6668: 6660: 6658: 6653: 6565:Oxidoreductases 6551: 6527:Enzyme kinetics 6515: 6511:List of enzymes 6484: 6453: 6424:Catalytic triad 6402: 6397: 6367: 6362: 6249: 6228:: Carbon-Sulfur 6220: 6102:: Carbon-Oxygen 6094: 6085:: CO CS and CN 6080: 6050: 6045: 6042: 6036: 6027: 6021: 6007: 6004: 5957: 5952: 5914: 5877: 5841: 5803: 5773: 5730: 5701: 5665:(6676): 605–8. 5656: 5620: 5608: 5598: 5586: 5565: 5535:(Pt 2): 373–7. 5522: 5479: 5436: 5395: 5364: 5327: 5306: 5269: 5248: 5244: 5242:Further reading 5239: 5201: 5200: 5196: 5173:(20): 2587–97. 5160: 5159: 5155: 5132:(51): 35783–8. 5119: 5118: 5114: 5083: 5082: 5078: 5029: 5028: 5024: 5001:(12): 1427–37. 4988: 4987: 4983: 4939: 4938: 4934: 4898: 4897: 4886: 4842: 4841: 4834: 4798: 4797: 4793: 4770:(11): 6979–87. 4757: 4756: 4749: 4720:(13): 2839–43. 4707: 4706: 4702: 4648: 4647: 4643: 4606: 4605: 4601: 4564:Nature Genetics 4549: 4548: 4544: 4513: 4512: 4508: 4485:(24): 16193–6. 4472: 4471: 4467: 4444:(12): 1427–37. 4431: 4430: 4426: 4390: 4389: 4385: 4356:(10): 1144–50. 4350:Nature Medicine 4346: 4345: 4338: 4303:Nature Genetics 4299: 4298: 4294: 4259:Nature Genetics 4255: 4254: 4250: 4219:(19): 5256–64. 4206: 4205: 4201: 4163: 4162: 4158: 4119: 4118: 4114: 4072: 4071: 4067: 4021: 4020: 4016: 3991:10.1038/ncb1981 3972: 3971: 3962: 3925: 3924: 3920: 3876: 3875: 3871: 3848:10.1038/ncb2012 3833: 3832: 3828: 3774: 3773: 3769: 3738:(11): a011338. 3725: 3724: 3717: 3678:(7445): 372–6. 3665: 3664: 3657: 3613: 3612: 3608: 3556: 3555: 3551: 3507: 3506: 3497: 3451: 3450: 3443: 3399: 3398: 3394: 3348: 3347: 3340: 3303:(7503): 162–6. 3293: 3292: 3283: 3231: 3230: 3221: 3169: 3168: 3164: 3110: 3109: 3098: 3051: 3050: 3037: 3006:(11): 2076–88. 2993: 2992: 2977: 2941: 2940: 2936: 2906: 2905: 2901: 2864:(6676): 605–8. 2855: 2854: 2850: 2837: 2836: 2832: 2819: 2818: 2814: 2802: 2793: 2781: 2772: 2768: 2763: 2680:Alpha-synuclein 2668: 2587: 2518:neuroprotective 2479:skeletal muscle 2466:eukaryotic cell 2441:neurons in the 2435:locus coeruleus 2433:neurons in the 2411:alpha-synuclein 2353: 2348: 2275:and produces a 2219: 2097: 2092: 2075:crystallisation 2040:phosphorylation 2020:catalytic triad 1903: 1798:View/Edit Mouse 1793:View/Edit Human 1756: 1749: 1746:Location (UCSC) 1732: 1728: 1707: 1703: 1699: 1673: 1669: 1648: 1644: 1640: 1553:ENSG00000185345 1446: 895: 851:Golgi apparatus 794: 710:protein binding 660:tubulin binding 605: 574: 565: 560: 556: 552: 548: 544: 540: 536: 532: 528: 526:muscle of thigh 514: 503: 498: 494: 490: 486: 482: 480:Achilles tendon 478: 474: 472:muscle of thigh 470: 466: 452: 396: 383: 375: 365: 364: 363: 356: 336: 313:Gene location ( 295: 282: 274: 264: 263: 262: 255: 233: 210:Gene location ( 161: 148: 141: 90: 68: 34: 23: 22: 15: 12: 11: 5: 6710: 6708: 6700: 6699: 6694: 6684: 6683: 6679: 6678: 6655: 6654: 6652: 6651: 6638: 6625: 6612: 6599: 6586: 6573: 6559: 6557: 6553: 6552: 6550: 6549: 6544: 6539: 6534: 6529: 6523: 6521: 6517: 6516: 6514: 6513: 6508: 6503: 6498: 6492: 6490: 6489:Classification 6486: 6485: 6483: 6482: 6477: 6472: 6467: 6461: 6459: 6455: 6454: 6452: 6451: 6446: 6441: 6436: 6431: 6426: 6421: 6416: 6410: 6408: 6404: 6403: 6398: 6396: 6395: 6388: 6381: 6373: 6364: 6363: 6361: 6360: 6355: 6354: 6353: 6348: 6338: 6333: 6328: 6323: 6318: 6313: 6311:CTP synthetase 6308: 6303: 6302: 6301: 6296: 6291: 6286: 6281: 6276: 6266: 6260: 6258: 6251: 6250: 6248: 6247: 6242: 6237: 6231: 6229: 6222: 6221: 6219: 6218: 6217: 6216: 6211: 6206: 6201: 6196: 6191: 6186: 6181: 6176: 6171: 6166: 6161: 6156: 6151: 6146: 6141: 6136: 6131: 6126: 6121: 6116: 6105: 6103: 6096: 6095: 6081: 6079: 6078: 6071: 6064: 6056: 6047: 6046: 6044: 6043: 6037: 6030: 6028: 6022: 6015: 6012: 6009: 6008: 6005: 6003: 6002: 5995: 5988: 5980: 5974: 5973: 5966:parkin+protein 5963: 5956: 5955:External links 5953: 5951: 5950: 5912: 5875: 5839: 5801: 5771: 5749:10.1086/301934 5728: 5699: 5654: 5618: 5610:|journal= 5584: 5563: 5520: 5477: 5434: 5393: 5362: 5330:Human Genetics 5325: 5304: 5278:(4): 296–302. 5267: 5245: 5243: 5240: 5238: 5237: 5194: 5153: 5112: 5076: 5022: 4981: 4952:(7): 891–902. 4932: 4905:Molecular Cell 4884: 4832: 4791: 4747: 4700: 4641: 4620:(2): 298–307. 4599: 4576:10.1038/ng.491 4542: 4506: 4465: 4424: 4383: 4336: 4292: 4271:10.1038/ng1769 4248: 4199: 4156: 4112: 4065: 4014: 3985:(11): 1370–5. 3960: 3933:Molecular Cell 3918: 3869: 3826: 3767: 3715: 3655: 3606: 3549: 3520:(10): 989–99. 3495: 3441: 3392: 3338: 3281: 3219: 3162: 3096: 3035: 2975: 2954:(1–3): 55–72. 2934: 2899: 2848: 2830: 2812: 2791: 2769: 2767: 2764: 2762: 2761: 2755: 2749: 2743: 2737: 2731: 2725: 2719: 2713: 2707: 2701: 2695: 2689: 2683: 2676: 2667: 2664: 2614:incidence rate 2600:samples while 2586: 2585:Tumourigenesis 2583: 2548:vesicle fusion 2522:excitotoxicity 2511:catalytic site 2473:vulnerable to 2352: 2349: 2347: 2344: 2342:capabilities. 2324:Warburg effect 2277:dose-dependent 2218: 2215: 2125:depolarisation 2109:autophagosomes 2096: 2093: 2091: 2088: 1902: 1899: 1895:tumourigenesis 1835:ubiquitination 1805: 1804: 1801: 1800: 1795: 1785: 1784: 1778: 1777: 1774: 1773: 1771: 1769: 1762: 1761: 1754: 1747: 1743: 1742: 1739: 1738: 1724: 1723: 1717: 1714: 1713: 1695: 1694: 1688: 1684: 1683: 1680: 1679: 1665: 1664: 1658: 1655: 1654: 1636: 1635: 1629: 1625: 1624: 1621: 1620: 1612: 1611: 1605: 1602: 1601: 1593: 1592: 1586: 1580: 1579: 1576: 1575: 1567: 1566: 1560: 1557: 1556: 1548: 1547: 1541: 1535: 1534: 1531: 1530: 1522: 1521: 1515: 1512: 1511: 1503: 1502: 1496: 1490: 1489: 1484: 1479: 1475: 1474: 1464: 1463: 1460: 1459: 1448: 1447: 1445: 1444: 1439: 1434: 1429: 1424: 1419: 1414: 1409: 1404: 1399: 1394: 1389: 1384: 1379: 1374: 1369: 1364: 1359: 1354: 1349: 1344: 1339: 1334: 1329: 1324: 1319: 1314: 1309: 1304: 1299: 1294: 1289: 1284: 1279: 1274: 1269: 1264: 1259: 1254: 1249: 1244: 1239: 1234: 1229: 1224: 1219: 1214: 1209: 1204: 1199: 1194: 1189: 1184: 1179: 1174: 1169: 1164: 1159: 1154: 1149: 1144: 1139: 1134: 1129: 1124: 1119: 1114: 1109: 1104: 1099: 1094: 1089: 1084: 1079: 1074: 1069: 1064: 1059: 1054: 1049: 1044: 1039: 1034: 1029: 1027:macroautophagy 1024: 1019: 1014: 1009: 1004: 999: 994: 989: 984: 979: 974: 969: 964: 959: 954: 949: 944: 939: 934: 929: 924: 919: 914: 909: 903: 901: 897: 896: 894: 893: 888: 883: 878: 873: 868: 863: 858: 853: 848: 843: 838: 833: 828: 823: 818: 813: 808: 802: 800: 796: 795: 793: 792: 787: 782: 777: 772: 767: 762: 757: 752: 747: 742: 737: 732: 727: 722: 717: 712: 707: 702: 697: 695:enzyme binding 692: 690:kinase binding 687: 682: 677: 672: 667: 662: 657: 652: 647: 642: 636: 634: 630: 629: 619: 618: 615: 614: 611: 610: 602: 601: 590: 584: 583: 580: 579: 571: 570: 567: 566: 564: 563: 559: 555: 551: 547: 543: 539: 535: 531: 527: 523: 520: 519: 508: 505: 504: 502: 501: 497: 493: 489: 485: 481: 477: 473: 469: 465: 461: 458: 457: 445: 444: 436: 425: 419: 418: 415:RNA expression 407: 406: 403: 402: 394: 390: 389: 381: 378: 373: 367: 366: 357: 350: 344: 340: 339: 334: 328: 327: 319: 318: 306: 305: 302: 301: 293: 289: 288: 280: 277: 272: 266: 265: 256: 249: 243: 239: 238: 231: 225: 224: 216: 215: 203: 202: 159: 155: 154: 146: 138: 137: 133: 132: 129: 128: 125: 124: 86: 85: 77: 76: 65: 59: 58: 50: 49: 41: 40: 24: 14: 13: 10: 9: 6: 4: 3: 2: 6709: 6698: 6695: 6693: 6690: 6689: 6687: 6677: 6672: 6667: 6663: 6649: 6645: 6644: 6639: 6636: 6632: 6631: 6626: 6623: 6619: 6618: 6613: 6610: 6606: 6605: 6600: 6597: 6593: 6592: 6587: 6584: 6580: 6579: 6574: 6571: 6567: 6566: 6561: 6560: 6558: 6554: 6548: 6545: 6543: 6540: 6538: 6535: 6533: 6530: 6528: 6525: 6524: 6522: 6518: 6512: 6509: 6507: 6506:Enzyme family 6504: 6502: 6499: 6497: 6494: 6493: 6491: 6487: 6481: 6478: 6476: 6473: 6471: 6470:Cooperativity 6468: 6466: 6463: 6462: 6460: 6456: 6450: 6447: 6445: 6442: 6440: 6437: 6435: 6432: 6430: 6429:Oxyanion hole 6427: 6425: 6422: 6420: 6417: 6415: 6412: 6411: 6409: 6405: 6401: 6394: 6389: 6387: 6382: 6380: 6375: 6374: 6371: 6359: 6356: 6352: 6349: 6347: 6344: 6343: 6342: 6339: 6337: 6334: 6332: 6329: 6327: 6324: 6322: 6319: 6317: 6314: 6312: 6309: 6307: 6304: 6300: 6297: 6295: 6292: 6290: 6287: 6285: 6282: 6280: 6277: 6275: 6272: 6271: 6270: 6267: 6265: 6262: 6261: 6259: 6256: 6252: 6246: 6243: 6241: 6238: 6236: 6233: 6232: 6230: 6227: 6223: 6215: 6212: 6210: 6207: 6205: 6202: 6200: 6197: 6195: 6192: 6190: 6187: 6185: 6184:Phenylalanine 6182: 6180: 6177: 6175: 6172: 6170: 6167: 6165: 6162: 6160: 6157: 6155: 6152: 6150: 6147: 6145: 6142: 6140: 6137: 6135: 6132: 6130: 6127: 6125: 6122: 6120: 6117: 6115: 6112: 6111: 6110: 6107: 6106: 6104: 6101: 6097: 6092: 6088: 6084: 6077: 6072: 6070: 6065: 6063: 6058: 6057: 6054: 6040: 6034: 6029: 6025: 6019: 6014: 6010: 6001: 5996: 5994: 5989: 5987: 5982: 5981: 5978: 5971: 5967: 5964: 5962: 5959: 5958: 5954: 5947: 5943: 5939: 5935: 5931: 5927: 5924:(5): 668–72. 5923: 5919: 5913: 5909: 5905: 5901: 5897: 5893: 5889: 5885: 5881: 5876: 5872: 5868: 5863: 5858: 5855:(4): 567–74. 5854: 5850: 5846: 5840: 5836: 5832: 5828: 5824: 5820: 5816: 5812: 5808: 5802: 5798: 5794: 5790: 5786: 5782: 5778: 5772: 5768: 5764: 5759: 5754: 5750: 5746: 5742: 5738: 5734: 5729: 5725: 5721: 5717: 5713: 5709: 5705: 5700: 5696: 5692: 5688: 5684: 5680: 5679:10.1038/33416 5676: 5672: 5668: 5664: 5660: 5655: 5651: 5647: 5642: 5637: 5634:(3): 588–96. 5633: 5629: 5625: 5619: 5615: 5603: 5595: 5591: 5587: 5581: 5577: 5573: 5569: 5564: 5560: 5556: 5551: 5546: 5542: 5538: 5534: 5530: 5526: 5521: 5517: 5513: 5508: 5503: 5499: 5495: 5492:(2): 235–42. 5491: 5487: 5483: 5478: 5474: 5470: 5465: 5460: 5456: 5452: 5448: 5444: 5440: 5435: 5431: 5427: 5423: 5419: 5415: 5411: 5407: 5403: 5399: 5394: 5390: 5386: 5381: 5376: 5372: 5368: 5363: 5359: 5355: 5351: 5347: 5343: 5339: 5336:(4): 327–36. 5335: 5331: 5326: 5322: 5318: 5314: 5310: 5305: 5301: 5297: 5293: 5289: 5285: 5281: 5277: 5273: 5268: 5264: 5260: 5256: 5252: 5247: 5246: 5241: 5233: 5229: 5225: 5221: 5217: 5213: 5209: 5205: 5198: 5195: 5190: 5186: 5181: 5176: 5172: 5168: 5164: 5157: 5154: 5149: 5145: 5140: 5135: 5131: 5127: 5123: 5116: 5113: 5108: 5104: 5100: 5096: 5093:(2): 179–89. 5092: 5088: 5080: 5077: 5072: 5068: 5064: 5060: 5055: 5050: 5046: 5042: 5038: 5034: 5026: 5023: 5018: 5014: 5009: 5004: 5000: 4996: 4992: 4985: 4982: 4977: 4973: 4969: 4965: 4960: 4955: 4951: 4947: 4943: 4936: 4933: 4928: 4924: 4919: 4914: 4910: 4906: 4902: 4895: 4893: 4891: 4889: 4885: 4880: 4876: 4872: 4868: 4863: 4858: 4855:(5): 735–49. 4854: 4850: 4846: 4839: 4837: 4833: 4828: 4824: 4819: 4814: 4811:(1): 486–91. 4810: 4806: 4802: 4795: 4792: 4787: 4783: 4778: 4773: 4769: 4765: 4761: 4754: 4752: 4748: 4743: 4739: 4735: 4731: 4727: 4723: 4719: 4715: 4711: 4704: 4701: 4696: 4692: 4687: 4682: 4677: 4672: 4668: 4664: 4660: 4656: 4652: 4645: 4642: 4637: 4633: 4628: 4623: 4619: 4615: 4611: 4603: 4600: 4595: 4591: 4586: 4581: 4577: 4573: 4569: 4565: 4561: 4557: 4553: 4546: 4543: 4538: 4534: 4530: 4526: 4522: 4518: 4510: 4507: 4502: 4498: 4493: 4488: 4484: 4480: 4476: 4469: 4466: 4461: 4457: 4452: 4447: 4443: 4439: 4435: 4428: 4425: 4420: 4416: 4411: 4406: 4402: 4398: 4394: 4387: 4384: 4379: 4375: 4371: 4367: 4363: 4359: 4355: 4351: 4343: 4341: 4337: 4332: 4328: 4324: 4320: 4316: 4315:10.1038/77060 4312: 4308: 4304: 4296: 4293: 4288: 4284: 4280: 4276: 4272: 4268: 4264: 4260: 4252: 4249: 4244: 4240: 4235: 4230: 4226: 4222: 4218: 4214: 4210: 4203: 4200: 4195: 4191: 4187: 4183: 4179: 4175: 4171: 4167: 4160: 4157: 4152: 4148: 4144: 4140: 4136: 4132: 4129:(2): 176–85. 4128: 4124: 4116: 4113: 4108: 4104: 4100: 4096: 4092: 4088: 4084: 4080: 4076: 4069: 4066: 4061: 4057: 4053: 4049: 4045: 4041: 4037: 4033: 4029: 4025: 4018: 4015: 4010: 4006: 4001: 3996: 3992: 3988: 3984: 3980: 3976: 3969: 3967: 3965: 3961: 3956: 3952: 3947: 3942: 3939:(5): 908–21. 3938: 3934: 3930: 3922: 3919: 3914: 3910: 3905: 3900: 3896: 3892: 3888: 3884: 3880: 3873: 3870: 3865: 3861: 3857: 3853: 3849: 3845: 3842:(2): 119–31. 3841: 3837: 3830: 3827: 3822: 3818: 3813: 3808: 3803: 3798: 3794: 3790: 3786: 3782: 3778: 3771: 3768: 3763: 3759: 3754: 3749: 3745: 3741: 3737: 3733: 3729: 3722: 3720: 3716: 3711: 3707: 3702: 3697: 3693: 3689: 3685: 3681: 3677: 3673: 3669: 3662: 3660: 3656: 3651: 3647: 3642: 3637: 3633: 3629: 3626:(2): 433–46. 3625: 3621: 3617: 3610: 3607: 3602: 3598: 3593: 3588: 3584: 3580: 3576: 3572: 3568: 3564: 3560: 3553: 3550: 3545: 3541: 3536: 3531: 3527: 3523: 3519: 3515: 3511: 3504: 3502: 3500: 3496: 3491: 3487: 3482: 3477: 3472: 3467: 3463: 3459: 3455: 3448: 3446: 3442: 3437: 3433: 3428: 3423: 3419: 3415: 3411: 3407: 3403: 3396: 3393: 3388: 3384: 3379: 3374: 3369: 3364: 3360: 3356: 3352: 3345: 3343: 3339: 3334: 3330: 3326: 3322: 3318: 3314: 3310: 3306: 3302: 3298: 3290: 3288: 3286: 3282: 3277: 3273: 3268: 3263: 3259: 3255: 3251: 3247: 3243: 3239: 3235: 3228: 3226: 3224: 3220: 3215: 3211: 3207: 3203: 3198: 3193: 3189: 3185: 3181: 3177: 3173: 3166: 3163: 3158: 3154: 3149: 3144: 3139: 3134: 3130: 3126: 3122: 3118: 3114: 3107: 3105: 3103: 3101: 3097: 3092: 3088: 3083: 3078: 3074: 3070: 3066: 3062: 3058: 3054: 3048: 3046: 3044: 3042: 3040: 3036: 3031: 3027: 3022: 3017: 3013: 3009: 3005: 3001: 2997: 2990: 2988: 2986: 2984: 2982: 2980: 2976: 2971: 2967: 2962: 2957: 2953: 2949: 2945: 2938: 2935: 2930: 2926: 2922: 2918: 2914: 2910: 2903: 2900: 2895: 2891: 2887: 2883: 2879: 2878:10.1038/33416 2875: 2871: 2867: 2863: 2859: 2852: 2849: 2844: 2840: 2834: 2831: 2826: 2822: 2816: 2813: 2809: 2805: 2800: 2798: 2796: 2792: 2788: 2784: 2779: 2777: 2775: 2771: 2765: 2759: 2756: 2753: 2750: 2747: 2744: 2741: 2738: 2735: 2732: 2729: 2726: 2723: 2720: 2717: 2714: 2711: 2708: 2705: 2702: 2699: 2696: 2693: 2690: 2687: 2684: 2681: 2678: 2677: 2675: 2673: 2665: 2663: 2661: 2657: 2653: 2649: 2646: 2642: 2638: 2634: 2630: 2629:breast cancer 2626: 2623: 2619: 2615: 2611: 2607: 2603: 2599: 2595: 2592: 2584: 2582: 2580: 2576: 2572: 2568: 2563: 2561: 2557: 2553: 2549: 2545: 2541: 2537: 2533: 2532: 2527: 2523: 2519: 2514: 2512: 2508: 2504: 2498: 2496: 2492: 2488: 2484: 2480: 2476: 2475:neurotoxicity 2471: 2467: 2462: 2460: 2456: 2452: 2448: 2444: 2440: 2436: 2432: 2431:noradrenergic 2428: 2427:pathognomonic 2424: 2423:ubiquitinated 2420: 2416: 2412: 2408: 2404: 2400: 2396: 2395: 2390: 2386: 2381: 2379: 2375: 2371: 2368: 2364: 2361: 2357: 2345: 2343: 2341: 2337: 2333: 2329: 2325: 2321: 2317: 2313: 2309: 2305: 2301: 2297: 2294: 2290: 2286: 2282: 2281:pro-apoptotic 2278: 2274: 2271: 2266: 2264: 2260: 2256: 2252: 2248: 2244: 2240: 2236: 2235:transcription 2232: 2228: 2224: 2217:Cell survival 2216: 2214: 2212: 2208: 2203: 2199: 2195: 2190: 2188: 2185: 2181: 2177: 2173: 2169: 2165: 2161: 2158: 2154: 2150: 2146: 2142: 2138: 2133: 2131: 2126: 2122: 2118: 2114: 2110: 2106: 2102: 2094: 2089: 2087: 2084: 2080: 2076: 2071: 2069: 2065: 2061: 2058:destabilises 2057: 2053: 2049: 2045: 2041: 2036: 2031: 2029: 2025: 2021: 2017: 2013: 2009: 2005: 2001: 1993: 1992:stoichiometry 1988: 1984: 1980: 1976: 1974: 1970: 1966: 1962: 1958: 1954: 1950: 1949:synaptotagmin 1946: 1942: 1938: 1934: 1930: 1927: 1923: 1920:However, how 1918: 1916: 1912: 1908: 1900: 1898: 1896: 1892: 1889:and aberrant 1888: 1884: 1880: 1876: 1872: 1867: 1864: 1860: 1856: 1852: 1848: 1844: 1840: 1836: 1832: 1829: 1825: 1821: 1818: 1815: 1811: 1799: 1794: 1790: 1786: 1783: 1779: 1772: 1770: 1767: 1763: 1759: 1755: 1752: 1748: 1744: 1737: 1735: 1731: 1725: 1721: 1718: 1712: 1710: 1706: 1702: 1696: 1692: 1689: 1685: 1678: 1676: 1672: 1666: 1662: 1659: 1653: 1651: 1647: 1643: 1637: 1633: 1630: 1628:RefSeq (mRNA) 1626: 1619: 1618: 1613: 1609: 1606: 1600: 1599: 1594: 1590: 1587: 1585: 1581: 1574: 1573: 1568: 1564: 1561: 1555: 1554: 1549: 1545: 1542: 1540: 1536: 1529: 1528: 1523: 1519: 1516: 1510: 1509: 1504: 1500: 1497: 1495: 1491: 1488: 1485: 1483: 1480: 1476: 1473: 1469: 1465: 1458: 1454: 1449: 1443: 1440: 1438: 1435: 1433: 1430: 1428: 1425: 1423: 1420: 1418: 1415: 1413: 1410: 1408: 1405: 1403: 1400: 1398: 1395: 1393: 1390: 1388: 1385: 1383: 1380: 1378: 1375: 1373: 1370: 1368: 1365: 1363: 1360: 1358: 1355: 1353: 1350: 1348: 1345: 1343: 1340: 1338: 1335: 1333: 1330: 1328: 1325: 1323: 1320: 1318: 1315: 1313: 1310: 1308: 1305: 1303: 1300: 1298: 1295: 1293: 1290: 1288: 1285: 1283: 1280: 1278: 1275: 1273: 1270: 1268: 1265: 1263: 1260: 1258: 1255: 1253: 1250: 1248: 1245: 1243: 1240: 1238: 1235: 1233: 1230: 1228: 1225: 1223: 1220: 1218: 1215: 1213: 1210: 1208: 1205: 1203: 1200: 1198: 1195: 1193: 1190: 1188: 1185: 1183: 1180: 1178: 1175: 1173: 1170: 1168: 1165: 1163: 1160: 1158: 1155: 1153: 1150: 1148: 1145: 1143: 1140: 1138: 1135: 1133: 1130: 1128: 1125: 1123: 1120: 1118: 1115: 1113: 1110: 1108: 1105: 1103: 1100: 1098: 1095: 1093: 1090: 1088: 1085: 1083: 1080: 1078: 1075: 1073: 1070: 1068: 1065: 1063: 1060: 1058: 1055: 1053: 1050: 1048: 1045: 1043: 1040: 1038: 1035: 1033: 1030: 1028: 1025: 1023: 1020: 1018: 1015: 1013: 1010: 1008: 1005: 1003: 1000: 998: 995: 993: 990: 988: 985: 983: 980: 978: 975: 973: 970: 968: 965: 963: 960: 958: 955: 953: 950: 948: 945: 943: 940: 938: 935: 933: 930: 928: 925: 923: 920: 918: 915: 913: 910: 908: 905: 904: 902: 899: 898: 892: 889: 887: 886:nuclear speck 884: 882: 879: 877: 874: 872: 869: 867: 866:LUBAC complex 864: 862: 859: 857: 854: 852: 849: 847: 844: 842: 839: 837: 834: 832: 829: 827: 824: 822: 819: 817: 816:mitochondrion 814: 812: 809: 807: 804: 803: 801: 798: 797: 791: 788: 786: 783: 781: 778: 776: 773: 771: 768: 766: 763: 761: 758: 756: 755:actin binding 753: 751: 748: 746: 743: 741: 738: 736: 733: 731: 728: 726: 723: 721: 718: 716: 713: 711: 708: 706: 703: 701: 698: 696: 693: 691: 688: 686: 683: 681: 678: 676: 673: 671: 668: 666: 663: 661: 658: 656: 653: 651: 648: 646: 643: 641: 638: 637: 635: 632: 631: 628: 627:Gene ontology 624: 620: 608: 603: 599: 594: 591: 589: 585: 577: 572: 561: 557: 553: 550:soleus muscle 549: 545: 541: 537: 533: 529: 525: 524: 521: 517: 512: 509: 499: 496:right auricle 495: 491: 487: 483: 479: 475: 471: 467: 463: 462: 459: 455: 450: 447: 446: 443: 441: 437: 435: 434: 430: 429: 426: 424: 420: 416: 412: 408: 400: 395: 391: 387: 382: 372: 368: 361: 354: 348: 341: 333: 329: 325: 320: 316: 311: 307: 299: 294: 290: 286: 281: 271: 267: 260: 253: 247: 240: 236: 230: 226: 222: 217: 213: 208: 204: 200: 196: 192: 188: 184: 180: 176: 172: 168: 164: 156: 151: 144: 139: 134: 123: 121: 117: 113: 109: 105: 101: 97: 93: 87: 82: 79: 78: 74: 71: 64: 60: 55: 51: 47: 42: 37: 32: 27: 19: 6643:Translocases 6640: 6627: 6614: 6601: 6588: 6578:Transferases 6575: 6562: 6419:Binding site 6331:GMP synthase 6038: 6023: 5921: 5917: 5886:(3): 180–2. 5883: 5879: 5852: 5848: 5810: 5806: 5783:(3): 754–8. 5780: 5776: 5743:(1): 88–94. 5740: 5736: 5710:(1): 143–6. 5707: 5703: 5662: 5658: 5631: 5627: 5567: 5532: 5528: 5489: 5485: 5449:(7): 681–5. 5446: 5443:EMBO Reports 5442: 5408:(1): 63–72. 5405: 5401: 5370: 5333: 5329: 5315:(6): 471–6. 5312: 5308: 5275: 5271: 5254: 5250: 5207: 5203: 5197: 5170: 5166: 5156: 5129: 5125: 5115: 5090: 5086: 5079: 5054:1721.1/96274 5039:(3): 521–5. 5036: 5033:FEBS Letters 5032: 5025: 4998: 4994: 4984: 4949: 4945: 4935: 4911:(1): 55–67. 4908: 4904: 4852: 4848: 4808: 4804: 4794: 4767: 4763: 4717: 4713: 4703: 4658: 4654: 4644: 4617: 4613: 4602: 4570:(1): 77–82. 4567: 4563: 4556:Cloughesy TF 4545: 4523:(3): 754–8. 4520: 4516: 4509: 4482: 4478: 4468: 4441: 4437: 4427: 4403:(3): 431–9. 4400: 4396: 4386: 4353: 4349: 4309:(3): 302–5. 4306: 4302: 4295: 4265:(5): 515–7. 4262: 4258: 4251: 4216: 4212: 4202: 4169: 4165: 4159: 4126: 4122: 4115: 4085:(1): 44–50. 4082: 4078: 4068: 4027: 4023: 4017: 3982: 3978: 3936: 3932: 3921: 3889:(6): 58–60. 3886: 3882: 3872: 3839: 3835: 3829: 3784: 3780: 3770: 3735: 3731: 3675: 3671: 3623: 3619: 3609: 3566: 3562: 3552: 3517: 3513: 3461: 3457: 3409: 3405: 3395: 3358: 3354: 3300: 3296: 3241: 3237: 3179: 3175: 3165: 3120: 3116: 3064: 3060: 3003: 2999: 2951: 2947: 2937: 2915:(1): 143–6. 2912: 2908: 2902: 2861: 2857: 2851: 2842: 2833: 2824: 2815: 2669: 2666:Interactions 2647: 2617: 2609: 2608:deletion of 2606:heterozygous 2602:lung cancers 2598:glioblastoma 2590: 2588: 2574: 2567:cytotoxicity 2564: 2542:complex and 2529: 2525: 2515: 2499: 2463: 2459:bradykinesia 2439:dopaminergic 2392: 2382: 2355: 2354: 2303: 2292: 2289:Transfection 2267: 2251:cytochrome C 2220: 2191: 2134: 2098: 2072: 2070:for parkin. 2032: 1997: 1986: 1982: 1939:, CDC-rel1, 1926:dopaminergic 1919: 1904: 1871:mitochondria 1868: 1827: 1809: 1808: 1730:NP_001304655 1727: 1698: 1675:NM_001317726 1668: 1639: 1615: 1596: 1570: 1551: 1525: 1506: 1486: 1481: 922:ERAD pathway 562:right kidney 534:spermatocyte 438: 431: 296:162,727,775 283:161,347,417 158:External IDs 89: 26: 6414:Active site 6006:PDB gallery 5257:(1): 83–8. 4714:NeuroReport 2758:Ubiquitin C 2594:copy number 2538:subunit of 2415:Lewy bodies 2385:Lewy bodies 2340:antioxidant 2328:glutathione 2316:respiration 2312:homeostasis 2243:translation 2184:hippocampal 2157:translocase 1965:PDZ domains 1937:synphilin-1 1911:degradation 1843:proteasomes 500:left testis 464:sural nerve 397:12,282,248 384:11,059,271 136:Identifiers 6686:Categories 6617:Isomerases 6591:Hydrolases 6458:Regulation 6204:Tryptophan 6179:Methionine 6164:Isoleucine 6124:Asparagine 5210:(1): 4–8. 4554:, Liau L, 4552:Mischel PS 2810:, May 2017 2789:, May 2017 2766:References 2637:metastatic 2633:epithelial 2562:function. 2447:idiopathic 2413:-enriched 2378:homozygous 2336:glycolytic 2245:maintains 2035:sterically 2024:N-terminal 1961:C-terminal 1933:hypothesis 1891:metabolism 1814:amino acid 871:presynapse 554:knee joint 442:(ortholog) 179:HomoloGene 6496:EC number 6199:Threonine 6159:Histidine 6149:Glutamine 6144:Glutamate 6129:Aspartate 5612:ignored ( 5602:cite book 4710:Wolozin B 3214:206548928 3053:Dawson TM 2641:prognosis 2503:catalysis 2487:complex I 2483:platelets 2401:forms of 2263:stressors 2198:cytosolic 2182:of mouse 2149:Proteomic 2101:mitophagy 2095:Mitophagy 2056:phosphate 2028:substrate 2016:glutamate 2012:histidine 1901:Structure 1883:Mutations 1879:apoptosis 1875:autophagy 1859:thioester 1847:lysosomes 1839:ubiquitin 1812:is a 465- 1734:NP_057903 1709:NP_054643 1705:NP_054642 1701:NP_004553 1671:NM_016694 1650:NM_013988 1646:NM_013987 1642:NM_004562 1472:Orthologs 1357:mitophagy 1317:autophagy 841:aggresome 831:Lewy body 806:cytoplasm 542:spermatid 187:GeneCards 6520:Kinetics 6444:Cofactor 6407:Activity 6209:Tyrosine 6134:Cysteine 6119:Arginine 6093:6.1-6.3) 5946:37299782 5938:10319893 5908:32794960 5900:10214987 5871:10072423 5835:44409075 5704:Genomics 5594:17017530 5559:16840513 5516:15717024 5473:15229644 5430:84671340 5422:14987449 5389:14976155 5358:23264061 5350:14727181 5321:12138708 5300:21068281 5292:12044248 5224:18541373 5189:12925569 5148:18845538 5107:14559152 5063:19146857 5017:12783850 4968:11439185 4927:12150907 4879:17024826 4871:12628165 4827:11679592 4786:18195004 4742:83941655 4734:11588587 4695:20696900 4636:16819513 4614:Oncogene 4594:19946270 4501:16672220 4460:12783850 4419:17981811 4378:12487644 4370:11590439 4323:10888878 4287:13956928 4279:16604074 4243:16687518 4194:28670790 4143:12891670 4107:85058092 4099:15266615 4060:36668814 4052:16728594 4009:19801972 3955:23453807 3913:23531882 3864:26096413 3856:20098416 3821:27679849 3762:23125018 3710:23503661 3650:18200046 3601:22936770 3544:25995186 3490:25759682 3436:23727886 3387:23754282 3325:24784582 3276:23770887 3244:: 1982. 3206:23661642 3157:21930938 3091:20187240 3030:25712550 2970:15571809 2909:Genomics 2806:– 2785:– 2672:interact 2399:sporadic 2296:promoter 2231:polymers 2211:CALCOCO2 2090:Function 2083:arginine 2068:affinity 2008:cysteine 1941:cyclin E 1782:Wikidata 1451:Sources: 977:learning 468:testicle 6676:Biology 6630:Ligases 6400:Enzymes 6189:Proline 6169:Leucine 6154:Glycine 6114:Alanine 6087:ligases 6083:Enzymes 5827:9802278 5797:9731209 5767:9634531 5758:1377254 5724:9570960 5695:4432261 5687:9560156 5667:Bibcode 5650:9042918 5641:1712507 5550:1819454 5486:NeuroRx 5464:1299099 5263:9014427 5232:2169911 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