419:, as the combination of calcins and ryanodine can have a cumulative effect on RyR1. Like most calcins, vejocalcin shows a fast association rate, as well as a reversible effect, due to free dissociation from the binding site. Single channel experiments and modeling of the kinetics and gating of RyR1 during calcin exposure suggest that the RyR1 transits between closed and open states and a single calcin molecule binds to the channel when the channel is in the open state. It is hypothesized that globular calcins, such as vejocalcin, can affect RyR1 channels by entering the cytosolic opening and accessing the binding site in the core of the channel. The precise mechanism by which calcins bind to their target, however, remains controversial.
387:(DM) and appears to be a prevalent feature across all toxins of the calcin family. Interestingly, vejocalcin has the smallest charge segregation among peptides in the calcin family. However, comparisons among different calcins show that, for each peptide, there appears to be no correlation between DM, binding affinity and subconductance state attributes.
27:
427:
Using single channel electrophysiological recordings, it was found that RyR1 channels exposed to vejocalcin move from an open state to a subconductance open state, with the latter conducting approximately 60% of the full-conductance level. Evidence from ryanodine binding assays shows that vejocalcin
520:
with high efficiency. Thus, they act as cell-penetrating peptides (CPPs) and can transport large, membrane-impermeable cargos across the plasma membrane directly into the cell. This property of calcins, combined with their high-affinity and specificity to RyRs, may have positive implications for
398:. Specifically, three disulfide bonds are formed between cysteine residues in positions 3–17, 10–21, and 16–32. These three disulfide bonds arrange themselves spatially to form a “disulfide through disulfide knot”, which is an evolutionary conserved structural motif known as the
882:
Fajloun Z, Kharrat R, Chen L, Lecomte C, Di Luccio E, Bichet D, El Ayeb M, Rochat H, Allen PD, Pessah IN, De Waard M, Sabatier JM (March 2000). "Chemical synthesis and characterization of maurocalcine, a scorpion toxin that activates Ca release channel/ryanodine receptors".
503:
has shown that the peptide induces neurotoxic symptoms in mice, followed by death. The comparable activity of vejocalcin and hemicalcin on RyR1 suggests a similar toxicity of vejocalcin. However, given the high variability in RyR-affinity between various calcins, the
382:
Vejocalcin shows an arrangement of charged residues, in which most of the positively charged residues are segregated on one side of the molecule, whereas neutral and negatively charged residues are clustered on the opposite side. This arrangement generates a discrete
402:
motif (ICK motif), thus defining the whole protein as a knottin. This three-dimensional arrangement confers the protein remarkable stability and builds the structural core of its pharmacological active site. ICK motifs have also been shown to be characteristic of
1030:
Boisseau S, Mabrouk K, Ram N, Garmy N, Collin V, Tadmouri A, Mikati M, Sabatier JM, Ronjat M, Fantini J, De Waard M (March 2006). "Cell penetration properties of maurocalcine, a natural venom peptide active on the intracellular ryanodine receptor".
254:
was originally described in 1836, vejocalcin was only isolated in 2016. This toxin was named after the scorpion that produces the peptide as well as its structural similarity to other toxins of the scorpion calcin family.
268:
On the basis of its amino acid structure, vejocalcin belongs to the family of scorpion calcin toxins, a group of selective, high-affinity membrane-permeable ligands of RyRs. Vejocalcin shares significant
447:= 3.7 ± 0.4 nM. Mechanistically, vejocalcin is thought to promote this action by increasing the “openness” of the channel in a long-lasting, reversible and transient manner.
981:"Maurocalcine and domain A of the II-III loop of the dihydropyridine receptor Cav 1.1 subunit share common binding sites on the skeletal ryanodine receptor"
579:
Xiao, Liang; Gurrola, Georgina B.; Zhang, Jing; Martin, Mario San; Zamudio, Fernando Z.; Possani, Lourival D.; Valdivia, HĂ©ctor H. (2014-01-28).
415:
Though the exact target of vejocalcin on RyR1 remains unclear, it is thought that calcins bind to RyR1 at a binding site different from that of
184:
375:, differing in only one amino acid at position 14 (Asn and Lys, respectively). Despite this marked similarity, vejocalcin exhibits a
649:
353:
Ala-Asp-Cys-Leu-Ala-His-Leu-Lys-Leu-Cys-Lys-Lys-Asn-Asn-Asp-Cys-Cys-Ser-Lys-Lys-Cys-Ser-Arg-Arg-Gly-Thr-Asn-Pro-Glu-Glu-Arg-Cys-Arg
487:
stores. These functional effects are also characteristic of other calcins as detected in structure–function relationship assays.
473:
391:
702:"Recombinant expression of Intrepicalcin from the scorpion Vaejovis intrepidus and its effect on skeletal ryanodine receptors"
829:
Shahbazzadeh D, Srairi-Abid N, Feng W, Ram N, Borchani L, Ronjat M, Akbari A, Pessah IN, De Waard M, El Ayeb M (May 2007).
461:
release from skeletal sarcoplasmic vesicles. High concentrations of vejocalcin drive incomplete, submaximal depletion of
1124:
979:
Altafaj X, Cheng W, Estève E, Urbani J, Grunwald D, Sabatier JM, Coronado R, De Waard M, Ronjat M (February 2005).
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216:
74:
581:"Structure-Function Relationship of Calcins, a Family of High-Affinity Peptide Ligands of Ryanodine Receptors"
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428:
is able to enhance ryanodine binding to RyR1. This effect of vejocalcin is dose-dependent and happens at all
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Schwartz EF, Capes EM, Diego-GarcĂa E, Zamudio FZ, Fuentes O, Possani LD, Valdivia HH (June 2009).
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Vargas-Jaimes L, Xiao L, Zhang J, Possani LD, Valdivia HH, Quintero-Hernández V (April 2017).
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Benkusky NA, Farrell EF, Valdivia HH (October 2004). "Ryanodine receptor channelopathies".
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Vejocalcin has a molecular mass of approximately 3.8 kDa and an isoelectric point of 9.3.
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Notably, two calcins produced by two closely related scorpions - vejocalcin from
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It is a relatively small protein, consisting of only 33 amino acids:
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681:. Vol. 3. Nürnberg: C. H. Zeh'sche Buchhandlung. pp. 17–104.
155:
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131:
99:
26:
1104:
932:
scorpion venom with pharmacological activity on ryanodine receptors"
756:"Approaching ryanodine receptor therapeutics from the calcin angle"
521:
intracellular drug delivery, particularly for the treatment of RyR
516:
Despite their highly ionized nature, calcins are able to penetrate
201:
679:
Die
Arachniden: Getreu nach der Natur abgebildet und beschrieben
505:
220:
126:
219:(CPP); it binds with high affinity and specificity to skeletal
379:
to RyR1 that is 4.7-fold higher than that of intrepicalcin.
640:
Fet, V.; Sissom, W.D.; Lowe, G.; Braunwalder, M.E. (2000).
495:
While the effects of vejocalcin have not yet been studied,
250:, a scorpion endemic to North and Central America. While
227:, thereby triggering calcium release from intracellular
835:
which is active on ryanodine-sensitive Ca2+ channels"
285:
Physical and chemical characteristics of vejocalcin
831:"Hemicalcin, a new toxin from the Iranian scorpion
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149:
137:
125:
113:
105:
95:
90:
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67:
57:
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36:
928:"Characterization of hadrucalcin, a peptide from
642:Catalog of the scorpions of the world (1758–1998)
407:blocking toxins produced by snails and spiders.
450:Noteworthy, vejocalcin triggers dose-dependent
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31:3-dimensional modelling of Vejocalcin toxin.
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200:(VjCa, also called Vejocalcine) is a
7:
371:- display a 97% similarity in their
754:Ramos-Franco J, Fill M (May 2016).
273:with other members of this family.
644:. New York Entomological Society.
390:Maturation of vejocalcin involves
14:
948:10.1111/j.1476-5381.2009.00147.x
211:. Vejocalcin is a member of the
25:
474:calcium-induced calcium release
392:post-translational modification
1:
905:10.1016/s0014-5793(00)01239-4
706:Biochim Biophys Acta Gen Subj
1045:10.1016/j.bbamem.2006.02.007
718:10.1016/j.bbagen.2017.01.032
472:load through the process of
305:Positively charged residues
302:Negatively charged residues
221:ryanodine receptor 1 (RYR1)
1151:
1080:10.1016/j.bbrc.2004.08.033
1068:Biochem Biophys Res Commun
476:(CICR) from intracellular
246:Vejocalcin is produced by
609:10.1016/j.bpj.2013.11.656
439:levels, with an apparent
166:
24:
508:may vary significantly.
217:cell-penetrating peptide
215:of toxins. It acts as a
815:. UniProt. 3 July 2019.
998:10.1074/jbc.C400433200
400:inhibitor cystine knot
225:sarcoplasmic reticulum
109:Scorpion Calcin Family
833:Hemiscorpius lepturus
772:10.1085/jgp.201611599
441:dissociation constant
106:Sequence Similarities
1033:Biochim Biophys Acta
813:P0DPT1 · CAVEJ_VAEME
499:toxicity testing of
242:Source and etymology
68:Taxonomic Identifier
897:2000FEBSL.469..179F
673:Koch, C.L. (1836).
601:2014BpJ...106..106X
585:Biophysical Journal
286:
271:sequence similarity
264:Homology and family
21:
1125:Ion channel toxins
1110:UniProt Vejocalcin
851:10.1042/BJ20061404
396:tertiary structure
358:Vaejovis mexicanus
284:
252:Vaejovis mexicanus
248:Vaejovis mexicanus
91:Family and Domains
62:Vaejovis mexicanus
37:Names and Taxonomy
930:Hadrurus gertschi
348:
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299:Molecular Volume
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81:Taxonomic Lineage
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1105:Knottin Database
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42:Recommended name
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1135:Scorpion toxins
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809:"Vejocalcin"
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1130:Neurotoxins
985:J Biol Chem
595:: 106–113.
150:Identifiers
1119:Categories
529:References
501:hemicalcin
369:intrepidus
198:Vejocalcin
50:Short name
45:Vejocalcin
20:Vejocalcin
885:FEBS Lett
839:Biochem J
687:809414722
660:693746669
417:ryanodine
277:Structure
259:Chemistry
209:mexicanus
120:IPR012632
1088:15336975
1053:16545341
1017:15591063
966:19389159
913:10713267
869:17291197
790:27114611
736:28159581
627:24411242
491:Toxicity
367:Vaejovis
344:9 (27%)
338:2,692.7
335:3,774.4
290:Formula
238:stores.
207:Vaejovis
115:InterPro
85:Vaejovis
58:Organism
1008:2712624
957:2707986
893:Bibcode
860:1868827
781:4845691
727:5329131
618:3907369
597:Bibcode
497:in vivo
394:of its
341:3 (9%)
223:of the
156:UniProt
144:PS60028
139:PROSITE
132:PF08099
100:Knottin
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411:Target
161:P0DPT1
96:Domain
72:993612
591:(2).
364:from
202:toxin
16:Toxin
1084:PMID
1049:PMID
1037:1758
1013:PMID
962:PMID
909:PMID
865:PMID
786:PMID
732:PMID
710:1861
683:OCLC
656:OCLC
646:ISBN
623:PMID
593:Cell
506:LD50
360:and
127:Pfam
53:VjCa
1076:doi
1072:322
1041:doi
1003:PMC
993:doi
989:280
952:PMC
944:doi
940:157
901:doi
889:469
855:PMC
847:doi
843:404
776:PMC
768:doi
764:147
722:PMC
714:doi
613:PMC
605:doi
589:106
332:33
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478:Ca
463:Ca
452:Ca
430:Ca
324:47
320:56
229:Ca
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445:d
443:K
328:6
326:S
322:O
318:N
314:H
310:C
186:e
179:t
172:v
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