475:. Although older data suggested that different forms of the gamma secretase complex could be differentially responsible for generating different amyloid beta isoforms, current evidence indicates that the C-terminus of amyloid beta is produced by a series of single-residue cleavages by the same gamma secretase complex. Earlier cleavage sites produce peptides of length 46 (zeta-cleavage) and 49 (epsilon-cleavage).
2622:
35:
339:
during assembly and maturation of the complex; a required activation step is in the autocatalytic cleavage of presenilin to N- and C-terminal fragments. Nicastrin's primary role is in maintaining the stability of the assembled complex and regulating intracellular protein trafficking. PEN-2 associates
1034:
Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P (April 2006). "TMP21 is a presenilin complex component that modulates
572:
De
Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999). "A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain".
462:
generation; gamma secretase can cleave APP in any of multiple sites to generate a peptide of variable length, most typically from 39 to 42 amino acids long, with Aβ40 the most common isoform and Aβ42 the most susceptible to
450:
reconstructions have allowed the visualization of the hypothesized internal pores of about 2 nanometres. In 2014, a three-dimensional structure of an intact human gamma-secretase complex was determined by
414:. Substrate recognition occurs via nicastrin ectodomain binding to the N-terminus of the target, which is then passed via a poorly understood process between the two presenilin fragments to a
340:
with the complex via binding of a transmembrane domain of presenilin and, among other possible roles, helps to stabilize the complex after presenilin proteolysis has generated the activated
847:
Sobhanifar, S; Schneider, B; Löhr, F; Gottstein, D; Ikeya, T; Mlynarczyk, K; Pulawski, W; Ghoshdastider, U; Kolinski, M; Filipek, S; Güntert, P; Bernhard, F; Dötsch, V (25 May 2010).
386:. The complexes are then transported to the late ER where they interact with and cleave their substrate proteins. Gamma secretase complexes have also been observed localized to the
1078:
Farfara D, Trudler D, Segev-Amzaled N, Galron R, Stein R, Frenkel D (November 2010). "g secretase component presenilin is important for microglia b-Amyloid clearance".
170:
471:
fibrillogenesis. Certain mutations in both APP and both types of human presenilin are associated with increased Aβ42 production and the early-onset genetic form of
114:
102:
1703:"Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase"
320:
risk factor for
Alzheimer's disease and modulates immune cell activity. In humans, two forms of presenilin and two forms of APH-1 have been identified in the
1701:
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (January 2004).
808:"Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide"
1484:
Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE, Ito A, Winblad B, Cowburn RF, Thyberg J, Ankarcrona M (December 2004).
1662:"Familial Alzheimer's disease mutations inhibit gamma-secretase-mediated liberation of beta-amyloid precursor protein carboxy-terminal fragment"
659:
Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK (2002).
616:
Ni CY, Murphy MP, Golde TE, Carpenter G (2001). "gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase".
2647:
2267:
1897:
20:
661:"A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions"
2341:
1336:
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (September 2010).
455:
single-particle analysis at 4.5 angstrom resolution and in 2015 an atomic-resolution (3.4 angstrom) cryo-EM structure was reported.
2252:
252:
patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as
2642:
1256:"Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex"
472:
710:"A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations"
2497:
190:
948:
Zhou S, Zhou H, Walian PJ, Jap BK (April 2006). "The discovery and role of CD147 as a subunit of gamma-secretase complex".
2183:
2098:
2612:
2116:
1562:"Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores"
1445:"Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway"
332:, leading to at least six different possible gamma secretase complexes that may have tissue- or cell type specificity.
1295:
Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, Pedersen K, Han W, Thomas P, Lundkvist J, Hao YH, Yu G (February 2004).
1164:"Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/γ-Secretase Components"
458:
The gamma secretase complex is unusual among proteases in having a "sloppy" cleavage site at the C-terminal site in
2657:
1162:
Zhang YW, Luo WJ, Wang H, Lin P, Vetrivel KS, Liao F, Li F, Wong PC, Farquhar MG, Thinakaran G, Xu H (April 2005).
2482:
1215:"Pen-2 is incorporated into the gamma-secretase complex through binding to transmembrane domain 4 of presenilin 1"
2598:
2585:
2572:
2559:
2546:
2533:
2520:
2299:
2215:
2138:
2108:
2090:
2043:
2008:
1936:
1923:
407:
367:
222:
210:
2492:
2446:
2389:
2078:
1914:
806:
Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C (2002).
452:
403:
56:
2257:
985:"CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production"
759:"Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling"
178:
2394:
2247:
2073:
1974:
1964:
1890:
349:
55:(green); lumenal membrane shown in red and cytoplasmic membrane shown in blue. The structure was solved by
2061:
1949:
363:
249:
218:
2415:
2334:
2068:
1969:
464:
443:
383:
214:
2487:
1297:"A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex"
174:
1381:
2242:
2051:
329:
2451:
2201:
2163:
2147:
447:
126:
1611:
Lu P, Bai XC, Ma D, Xie T, Yan C, Sun L, Yang G, Zhao Y, Zhou R, Scheres SH, Shi Y (August 2014).
2384:
2237:
2178:
2168:
2158:
1883:
1103:
1060:
930:
739:
641:
598:
325:
899:
402:
Gamma secretase is an internal protease that cleaves within the membrane-spanning domain of its
1486:"Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria"
2232:
2125:
1862:
1813:
1765:
1724:
1683:
1642:
1593:
1542:
1507:
1466:
1425:
1367:
1318:
1277:
1236:
1195:
1144:
1095:
1052:
1016:
965:
922:
880:
829:
788:
731:
690:
633:
590:
554:
519:
Bai, Xiao-chen; Yan, Chuangye; Yang, Guanghui; Lu, Peilong; Ma, Dan; Sun, Linfeng; Zhou, Rui;
309:
165:
1525:
Wolfe MS (July 2006). "The gamma-secretase complex: membrane-embedded proteolytic ensemble".
2430:
2425:
2399:
2327:
2282:
2277:
2153:
1852:
1844:
1803:
1795:
1755:
1714:
1673:
1632:
1624:
1583:
1573:
1534:
1497:
1456:
1415:
1357:
1349:
1308:
1267:
1226:
1185:
1175:
1134:
1087:
1044:
1006:
996:
957:
914:
870:
860:
819:
778:
770:
721:
680:
672:
625:
582:
544:
536:
382:
The gamma secretase complex is thought to assemble and mature via proteolysis in the early
157:
2652:
2477:
2461:
2374:
2272:
2227:
484:
411:
253:
241:
1402:
Capell A, Beher D, Prokop S, Steiner H, Kaether C, Shearman MS, Haass C (February 2005).
348:
fragments. APH-1, which is required for proteolytic activity, binds to the complex via a
2626:
2515:
2456:
2308:
1944:
1857:
1832:
1808:
1787:
1637:
1612:
1588:
1561:
1362:
1337:
1190:
1163:
1011:
984:
875:
848:
783:
758:
549:
524:
362:
Recent research has shown that the interaction of the gamma secretase complex with the
356:
245:
226:
107:
685:
660:
2636:
2420:
2379:
2219:
2021:
1799:
1760:
1743:
1678:
1661:
520:
435:
1123:"Identification of distinct gamma-secretase complexes with different APH-1 variants"
1107:
934:
645:
83:
2369:
1927:
1744:"The same gamma-secretase accounts for the multiple intramembrane cleavages of APP"
1213:
Watanabe N, Tomita T, Sato C, Kitamura T, Morohashi Y, Iwatsubo T (December 2005).
1064:
757:
Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK (2006).
743:
602:
496:
490:
459:
387:
371:
237:
153:
44:
1338:"Gamma-secretase activating protein, a therapeutic target for Alzheimer's disease"
131:
119:
961:
300:(presenilin enhancer 2). Recent evidence suggests that a fifth protein, known as
217:
at residues within the transmembrane domain. Proteases of this type are known as
95:
2593:
2528:
2364:
2173:
2120:
2056:
2016:
1875:
1848:
431:
419:
352:
336:
304:, is a non-essential regulator of the complex whose absence increases activity.
2621:
853:
Proceedings of the
National Academy of Sciences of the United States of America
849:"Structural investigation of the C-terminal catalytic fragment of presenilin 1"
726:
709:
708:
Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK (2003).
676:
427:
345:
341:
305:
265:
261:
230:
1660:
Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M (September 2005).
774:
2567:
2541:
1906:
1578:
1001:
865:
629:
423:
391:
313:
289:
269:
40:
1866:
1817:
1769:
1728:
1687:
1646:
1597:
1546:
1511:
1502:
1485:
1470:
1461:
1444:
1429:
1420:
1403:
1371:
1322:
1313:
1296:
1281:
1272:
1255:
1240:
1231:
1214:
1199:
1180:
1148:
1139:
1122:
1099:
1056:
1020:
969:
926:
884:
833:
824:
807:
792:
735:
694:
637:
594:
558:
1910:
1719:
1702:
317:
225:, a large integral membrane protein that, when cleaved by both gamma and
206:
90:
1628:
1353:
1048:
540:
468:
233:
1538:
1091:
918:
2580:
2350:
1996:
1989:
1984:
1560:
Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H (May 2006).
1404:"Gamma-secretase complex assembly within the early secretory pathway"
439:
321:
185:
426:
residue is located. The active site must contain water to carry out
335:
The proteins in the gamma secretase complex are heavily modified by
1788:"Proteolytic processing of Alzheimer's β-amyloid precursor protein"
2554:
2031:
2026:
1959:
1954:
586:
415:
301:
297:
293:
285:
284:
The gamma secretase complex consists of four individual proteins:
257:
52:
48:
1254:
Prokop S, Shirotani K, Edbauer D, Haass C, Steiner H (May 2004).
273:
147:
78:
2323:
1879:
34:
1121:
Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H (2004).
1831:
Haass, C; Kaether, C; Thinakaran, G; Sisodia, S (May 2012).
2319:
446:
structure of gamma secretase is available. Low-resolution
359:
and aids in initiating assembly of premature components.
900:"Assembly, trafficking and function of gamma-secretase"
221:. The most well-known substrate of gamma secretase is
2610:
1035:
gamma-secretase but not epsilon-secretase activity".
2506:
2470:
2439:
2408:
2357:
2298:
2214:
2194:
2137:
2107:
2089:
2042:
2007:
1935:
1922:
1443:Kim SH, Yin YI, Li YM, Sisodia SS (November 2004).
438:, although it is not well understood how water and
184:
164:
146:
141:
125:
113:
101:
89:
77:
69:
64:
27:
1786:Zhang, H; Ma, Q; Zhang, YW; Xu, H (January 2012).
1613:"Three-dimensional structure of human γ-secretase"
1380:
316:subunit; mutations in the presenilin gene a major
1742:Zhao G, Tan J, Mao G, Cui MZ, Xu X (March 2007).
1382:"Finding Suggests New Aim for Alzheimer's Drugs"
1833:"Trafficking and proteolytic processing of APP"
983:Zhou S, Zhou H, Walian PJ, Jap BK (May 2005).
2335:
1891:
1781:
1779:
8:
1837:Cold Spring Harbor Perspectives in Medicine
244:fibrillar form is the primary component of
2342:
2328:
2320:
1932:
1898:
1884:
1876:
525:"An atomic structure of human γ-secretase"
390:, where they may play a role in promoting
328:can also be expressed in two isoforms via
138:
33:
1856:
1807:
1759:
1718:
1677:
1636:
1587:
1577:
1501:
1460:
1419:
1361:
1312:
1271:
1230:
1189:
1179:
1138:
1010:
1000:
874:
864:
823:
782:
725:
684:
548:
2617:
508:
898:Kaether C, Haass C, Steiner H (2006).
24:
514:
512:
7:
442:exchange is effected, and as yet no
296:(anterior pharynx-defective 1), and
2268:Amyloid precursor protein secretase
434:environment in the interior of the
28:Gamma-secretase (Nicastrin subunit)
21:Amyloid precursor protein secretase
366:facilitates the gamma cleavage of
39:The gamma secretase complex, with
14:
1379:Gina Kolata (September 1, 2010).
2620:
2253:Proteasome endopeptidase complex
1800:10.1111/j.1471-4159.2011.07519.x
1761:10.1111/j.1471-4159.2006.04302.x
1679:10.1111/j.1471-4159.2005.03266.x
523:; Shi, Yigong (17 August 2015).
364:γ-secretase activating protein
1:
2117:Serine type carboxypeptidases
2099:Angiotensin-converting enzyme
142:Available protein structures:
1566:Proc. Natl. Acad. Sci. U.S.A
989:Proc. Natl. Acad. Sci. U.S.A
962:10.1358/dnp.2006.19.3.985932
473:familial Alzheimer's disease
73:Gamma-secretase, γ-secretase
1849:10.1101/cshperspect.a006270
213:, that cleaves single-pass
2674:
2648:Integral membrane proteins
727:10.1016/j.cell.2003.08.008
18:
2498:Michaelis–Menten kinetics
1792:Journal of Neurochemistry
499:, a γ-secretase inhibitor
493:, a γ-secretase inhibitor
487:, a γ-secretase inhibitor
408:amyloid precursor protein
368:amyloid precursor protein
229:, produces a short 37-43
223:amyloid precursor protein
211:integral membrane protein
137:
32:
2390:Diffusion-limited enzyme
2079:Tripeptidyl peptidase II
775:10.1038/sj.emboj.7601031
453:cryo-electron microscopy
57:cryo-electron microscopy
2248:Threonine endopeptidase
2074:Tripeptidyl peptidase I
1579:10.1073/pnas.0602321103
1002:10.1073/pnas.0502768102
866:10.1073/pnas.1000778107
677:10.1093/emboj/21.8.1948
630:10.1126/science.1065412
248:found in the brains of
219:intramembrane proteases
2238:Aspartic acid protease
2062:Dipeptidyl peptidase-4
1503:10.1074/jbc.M404500200
1462:10.1074/jbc.C400396200
1421:10.1074/jbc.M409106200
1314:10.1074/jbc.M309745200
1273:10.1074/jbc.M401789200
1232:10.1074/jbc.M509066200
1181:10.1074/jbc.M409467200
1140:10.1074/jbc.M405768200
825:10.1074/jbc.M206872200
465:conformational changes
215:transmembrane proteins
2483:Eadie–Hofstee diagram
2416:Allosteric regulation
2069:Tripeptidyl peptidase
1794:. 120 Suppl 1: 9–21.
444:X-ray crystallography
384:endoplasmic reticulum
280:Subunits and assembly
2493:Lineweaver–Burk plot
2243:Metalloendopeptidase
2148:Metalloexopeptidases
2052:Dipeptidyl peptidase
521:Scheres, Sjors H. W.
422:where the catalytic
406:proteins, including
378:Cellular trafficking
330:alternative splicing
2643:Alzheimer's disease
2258:HslU—HslV peptidase
2202:Metalloexopeptidase
1629:10.1038/nature13567
1354:10.1038/nature09325
1080:Annals of Neurology
1049:10.1038/nature04667
541:10.1038/nature14892
448:electron microscopy
250:Alzheimer's disease
205:is a multi-subunit
2452:Enzyme superfamily
2385:Enzyme promiscuity
1720:10.1093/hmg/ddh019
1387:The New York Times
950:Drug News Perspect
2658:Protein complexes
2608:
2607:
2317:
2316:
2266:Other/ungrouped:
2233:Cysteine protease
2210:
2209:
2128:
1623:(7513): 166–170.
1539:10.1021/bi060799c
1092:10.1002/ana.22191
1043:(7088): 1208–12.
919:10.1159/000095267
624:(5549): 2179–81.
535:(7568): 212–217.
324:; one of the APH
310:aspartyl protease
240:whose abnormally
200:
199:
196:
195:
191:structure summary
2665:
2625:
2624:
2616:
2488:Hanes–Woolf plot
2431:Enzyme activator
2426:Enzyme inhibitor
2400:Enzyme catalysis
2344:
2337:
2330:
2321:
2283:Beta-secretase 2
2278:Beta-secretase 1
2154:Carboxypeptidase
2150:
2126:
1933:
1900:
1893:
1886:
1877:
1871:
1870:
1860:
1828:
1822:
1821:
1811:
1783:
1774:
1773:
1763:
1739:
1733:
1732:
1722:
1698:
1692:
1691:
1681:
1657:
1651:
1650:
1640:
1608:
1602:
1601:
1591:
1581:
1557:
1551:
1550:
1522:
1516:
1515:
1505:
1496:(49): 51654–60.
1481:
1475:
1474:
1464:
1440:
1434:
1433:
1423:
1399:
1393:
1390:
1384:
1375:
1365:
1333:
1327:
1326:
1316:
1292:
1286:
1285:
1275:
1266:(22): 23255–61.
1251:
1245:
1244:
1234:
1225:(51): 41967–75.
1210:
1204:
1203:
1193:
1183:
1159:
1153:
1152:
1142:
1118:
1112:
1111:
1075:
1069:
1068:
1031:
1025:
1024:
1014:
1004:
995:(21): 7499–504.
980:
974:
973:
945:
939:
938:
907:Neurodegener Dis
904:
895:
889:
888:
878:
868:
844:
838:
837:
827:
803:
797:
796:
786:
754:
748:
747:
729:
705:
699:
698:
688:
656:
650:
649:
613:
607:
606:
581:(6727): 518–22.
569:
563:
562:
552:
516:
288:(presenilin-1),
139:
37:
25:
2673:
2672:
2668:
2667:
2666:
2664:
2663:
2662:
2633:
2632:
2631:
2619:
2611:
2609:
2604:
2516:Oxidoreductases
2502:
2478:Enzyme kinetics
2466:
2462:List of enzymes
2435:
2404:
2375:Catalytic triad
2353:
2348:
2318:
2313:
2294:
2288:Gamma secretase
2273:Alpha secretase
2228:Serine protease
2206:
2195:Other/ungrouped
2190:
2146:
2133:
2129:-Transpeptidase
2103:
2085:
2038:
2003:
1918:
1904:
1874:
1830:
1829:
1825:
1785:
1784:
1777:
1741:
1740:
1736:
1707:Hum. Mol. Genet
1700:
1699:
1695:
1672:(5): 1189–201.
1659:
1658:
1654:
1610:
1609:
1605:
1572:(18): 6889–94.
1559:
1558:
1554:
1524:
1523:
1519:
1483:
1482:
1478:
1455:(47): 48615–9.
1442:
1441:
1437:
1401:
1400:
1396:
1378:
1335:
1334:
1330:
1294:
1293:
1289:
1253:
1252:
1248:
1212:
1211:
1207:
1174:(17): 17020–6.
1161:
1160:
1156:
1133:(40): 41340–5.
1120:
1119:
1115:
1077:
1076:
1072:
1033:
1032:
1028:
982:
981:
977:
947:
946:
942:
913:(4–5): 275–83.
902:
897:
896:
892:
846:
845:
841:
818:(47): 44754–9.
805:
804:
800:
756:
755:
751:
707:
706:
702:
658:
657:
653:
615:
614:
610:
571:
570:
566:
518:
517:
510:
506:
485:DAPT (chemical)
481:
400:
380:
282:
246:amyloid plaques
203:Gamma secretase
103:OPM superfamily
60:
23:
17:
16:Type of protein
12:
11:
5:
2671:
2669:
2661:
2660:
2655:
2650:
2645:
2635:
2634:
2630:
2629:
2606:
2605:
2603:
2602:
2589:
2576:
2563:
2550:
2537:
2524:
2510:
2508:
2504:
2503:
2501:
2500:
2495:
2490:
2485:
2480:
2474:
2472:
2468:
2467:
2465:
2464:
2459:
2454:
2449:
2443:
2441:
2440:Classification
2437:
2436:
2434:
2433:
2428:
2423:
2418:
2412:
2410:
2406:
2405:
2403:
2402:
2397:
2392:
2387:
2382:
2377:
2372:
2367:
2361:
2359:
2355:
2354:
2349:
2347:
2346:
2339:
2332:
2324:
2315:
2314:
2312:
2311:
2309:Staphylokinase
2305:
2303:
2296:
2295:
2293:
2292:
2291:
2290:
2285:
2280:
2275:
2263:
2262:
2261:
2260:
2255:
2245:
2240:
2235:
2230:
2224:
2222:
2212:
2211:
2208:
2207:
2205:
2204:
2198:
2196:
2192:
2191:
2189:
2188:
2187:
2186:
2181:
2176:
2171:
2166:
2161:
2151:
2143:
2141:
2135:
2134:
2132:
2131:
2123:
2113:
2111:
2105:
2104:
2102:
2101:
2095:
2093:
2087:
2086:
2084:
2083:
2082:
2081:
2076:
2066:
2065:
2064:
2059:
2048:
2046:
2040:
2039:
2037:
2036:
2035:
2034:
2029:
2024:
2013:
2011:
2005:
2004:
2002:
2001:
2000:
1999:
1994:
1993:
1992:
1987:
1977:
1972:
1967:
1962:
1957:
1952:
1945:Aminopeptidase
1941:
1939:
1930:
1920:
1919:
1905:
1903:
1902:
1895:
1888:
1880:
1873:
1872:
1843:(5): a006270.
1823:
1775:
1754:(5): 1234–46.
1734:
1693:
1652:
1603:
1552:
1533:(26): 7931–9.
1517:
1476:
1435:
1394:
1392:
1391:
1328:
1307:(6): 4144–52.
1287:
1246:
1205:
1154:
1113:
1070:
1026:
975:
940:
890:
859:(21): 9644–9.
839:
798:
769:(6): 1242–52.
749:
700:
671:(8): 1948–56.
651:
608:
564:
507:
505:
502:
501:
500:
494:
488:
480:
477:
399:
396:
379:
376:
281:
278:
227:beta secretase
198:
197:
194:
193:
188:
182:
181:
168:
162:
161:
151:
144:
143:
135:
134:
129:
123:
122:
117:
111:
110:
105:
99:
98:
93:
87:
86:
81:
75:
74:
71:
67:
66:
62:
61:
38:
30:
29:
15:
13:
10:
9:
6:
4:
3:
2:
2670:
2659:
2656:
2654:
2651:
2649:
2646:
2644:
2641:
2640:
2638:
2628:
2623:
2618:
2614:
2600:
2596:
2595:
2590:
2587:
2583:
2582:
2577:
2574:
2570:
2569:
2564:
2561:
2557:
2556:
2551:
2548:
2544:
2543:
2538:
2535:
2531:
2530:
2525:
2522:
2518:
2517:
2512:
2511:
2509:
2505:
2499:
2496:
2494:
2491:
2489:
2486:
2484:
2481:
2479:
2476:
2475:
2473:
2469:
2463:
2460:
2458:
2457:Enzyme family
2455:
2453:
2450:
2448:
2445:
2444:
2442:
2438:
2432:
2429:
2427:
2424:
2422:
2421:Cooperativity
2419:
2417:
2414:
2413:
2411:
2407:
2401:
2398:
2396:
2393:
2391:
2388:
2386:
2383:
2381:
2380:Oxyanion hole
2378:
2376:
2373:
2371:
2368:
2366:
2363:
2362:
2360:
2356:
2352:
2345:
2340:
2338:
2333:
2331:
2326:
2325:
2322:
2310:
2307:
2306:
2304:
2301:
2297:
2289:
2286:
2284:
2281:
2279:
2276:
2274:
2271:
2270:
2269:
2265:
2264:
2259:
2256:
2254:
2251:
2250:
2249:
2246:
2244:
2241:
2239:
2236:
2234:
2231:
2229:
2226:
2225:
2223:
2221:
2220:Endopeptidase
2217:
2213:
2203:
2200:
2199:
2197:
2193:
2185:
2182:
2180:
2177:
2175:
2172:
2170:
2167:
2165:
2162:
2160:
2157:
2156:
2155:
2152:
2149:
2145:
2144:
2142:
2140:
2136:
2130:
2124:
2122:
2118:
2115:
2114:
2112:
2110:
2106:
2100:
2097:
2096:
2094:
2092:
2088:
2080:
2077:
2075:
2072:
2071:
2070:
2067:
2063:
2060:
2058:
2055:
2054:
2053:
2050:
2049:
2047:
2045:
2041:
2033:
2030:
2028:
2025:
2023:
2020:
2019:
2018:
2015:
2014:
2012:
2010:
2006:
1998:
1995:
1991:
1988:
1986:
1983:
1982:
1981:
1978:
1976:
1973:
1971:
1968:
1966:
1963:
1961:
1958:
1956:
1953:
1951:
1948:
1947:
1946:
1943:
1942:
1940:
1938:
1934:
1931:
1929:
1925:
1921:
1916:
1912:
1908:
1901:
1896:
1894:
1889:
1887:
1882:
1881:
1878:
1868:
1864:
1859:
1854:
1850:
1846:
1842:
1838:
1834:
1827:
1824:
1819:
1815:
1810:
1805:
1801:
1797:
1793:
1789:
1782:
1780:
1776:
1771:
1767:
1762:
1757:
1753:
1749:
1745:
1738:
1735:
1730:
1726:
1721:
1716:
1713:(2): 159–70.
1712:
1708:
1704:
1697:
1694:
1689:
1685:
1680:
1675:
1671:
1667:
1663:
1656:
1653:
1648:
1644:
1639:
1634:
1630:
1626:
1622:
1618:
1614:
1607:
1604:
1599:
1595:
1590:
1585:
1580:
1575:
1571:
1567:
1563:
1556:
1553:
1548:
1544:
1540:
1536:
1532:
1528:
1521:
1518:
1513:
1509:
1504:
1499:
1495:
1491:
1490:J. Biol. Chem
1487:
1480:
1477:
1472:
1468:
1463:
1458:
1454:
1450:
1449:J. Biol. Chem
1446:
1439:
1436:
1431:
1427:
1422:
1417:
1414:(8): 6471–8.
1413:
1409:
1408:J. Biol. Chem
1405:
1398:
1395:
1388:
1383:
1377:
1376:
1373:
1369:
1364:
1359:
1355:
1351:
1347:
1343:
1339:
1332:
1329:
1324:
1320:
1315:
1310:
1306:
1302:
1301:J. Biol. Chem
1298:
1291:
1288:
1283:
1279:
1274:
1269:
1265:
1261:
1260:J. Biol. Chem
1257:
1250:
1247:
1242:
1238:
1233:
1228:
1224:
1220:
1219:J. Biol. Chem
1216:
1209:
1206:
1201:
1197:
1192:
1187:
1182:
1177:
1173:
1169:
1168:J. Biol. Chem
1165:
1158:
1155:
1150:
1146:
1141:
1136:
1132:
1128:
1124:
1117:
1114:
1109:
1105:
1101:
1097:
1093:
1089:
1086:(1): 170–80.
1085:
1081:
1074:
1071:
1066:
1062:
1058:
1054:
1050:
1046:
1042:
1038:
1030:
1027:
1022:
1018:
1013:
1008:
1003:
998:
994:
990:
986:
979:
976:
971:
967:
963:
959:
955:
951:
944:
941:
936:
932:
928:
924:
920:
916:
912:
908:
901:
894:
891:
886:
882:
877:
872:
867:
862:
858:
854:
850:
843:
840:
835:
831:
826:
821:
817:
813:
809:
802:
799:
794:
790:
785:
780:
776:
772:
768:
764:
760:
753:
750:
745:
741:
737:
733:
728:
723:
720:(5): 635–45.
719:
715:
711:
704:
701:
696:
692:
687:
682:
678:
674:
670:
666:
662:
655:
652:
647:
643:
639:
635:
631:
627:
623:
619:
612:
609:
604:
600:
596:
592:
588:
587:10.1038/19083
584:
580:
576:
568:
565:
560:
556:
551:
546:
542:
538:
534:
530:
526:
522:
515:
513:
509:
503:
498:
495:
492:
489:
486:
483:
482:
478:
476:
474:
470:
466:
461:
456:
454:
449:
445:
441:
437:
436:cell membrane
433:
429:
425:
421:
417:
413:
409:
405:
397:
395:
393:
389:
385:
377:
375:
373:
369:
365:
360:
358:
354:
351:
347:
343:
338:
333:
331:
327:
323:
319:
315:
311:
307:
303:
299:
295:
291:
287:
279:
277:
275:
271:
267:
263:
259:
255:
251:
247:
243:
239:
235:
232:
228:
224:
220:
216:
212:
208:
204:
192:
189:
187:
183:
180:
176:
172:
169:
167:
163:
159:
155:
152:
149:
145:
140:
136:
133:
130:
128:
124:
121:
118:
116:
112:
109:
106:
104:
100:
97:
94:
92:
88:
85:
82:
80:
76:
72:
68:
63:
58:
54:
50:
46:
42:
36:
31:
26:
22:
2594:Translocases
2591:
2578:
2565:
2552:
2539:
2529:Transferases
2526:
2513:
2370:Binding site
2287:
2184:Glutamate II
1979:
1928:Exopeptidase
1840:
1836:
1826:
1791:
1751:
1748:J. Neurochem
1747:
1737:
1710:
1706:
1696:
1669:
1666:J. Neurochem
1665:
1655:
1620:
1616:
1606:
1569:
1565:
1555:
1530:
1527:Biochemistry
1526:
1520:
1493:
1489:
1479:
1452:
1448:
1438:
1411:
1407:
1397:
1386:
1348:(2): 95–98.
1345:
1341:
1331:
1304:
1300:
1290:
1263:
1259:
1249:
1222:
1218:
1208:
1171:
1167:
1157:
1130:
1126:
1116:
1083:
1079:
1073:
1040:
1036:
1029:
992:
988:
978:
956:(3): 133–8.
953:
949:
943:
910:
906:
893:
856:
852:
842:
815:
811:
801:
766:
762:
752:
717:
713:
703:
668:
664:
654:
621:
617:
611:
578:
574:
567:
532:
528:
497:Semagacestat
491:Nirogacestat
460:amyloid beta
457:
418:-containing
401:
388:mitochondria
381:
361:
355:interaction
334:
283:
238:amyloid beta
209:complex, an
202:
201:
51:(blue), and
45:presenilin-1
2365:Active site
2121:Cathepsin A
2057:Cathepsin C
2017:Dipeptidase
1127:J Biol Chem
812:J Biol Chem
467:leading to
432:hydrophobic
420:active site
353:alpha helix
337:proteolysis
115:OPM protein
65:Identifiers
2637:Categories
2568:Isomerases
2542:Hydrolases
2409:Regulation
504:References
428:hydrolysis
410:(APP) and
346:C-terminal
342:N-terminal
306:Presenilin
266:N-cadherin
262:E-cadherin
231:amino acid
154:structures
127:Membranome
47:(orange),
19:See also:
2447:EC number
2302:: Unknown
1980:Methionyl
1911:proteases
1907:Hydrolase
430:within a
424:aspartate
404:substrate
392:apoptosis
372:β-amyloid
350:conserved
314:catalytic
312:, is the
290:nicastrin
270:ephrin-B2
96:IPR008710
41:nicastrin
2471:Kinetics
2395:Cofactor
2358:Activity
1975:Glutamyl
1965:Cystinyl
1960:Aspartyl
1867:22553493
1818:22122372
1770:17241131
1729:14645205
1688:15992373
1647:25043039
1598:16636269
1547:16800619
1512:15456764
1471:15456788
1430:15591316
1372:20811458
1323:14627705
1282:15039426
1241:16234244
1200:15711015
1149:15286082
1108:20603724
1100:21280087
1057:16641999
1021:15890777
970:16804564
935:17324271
927:17047368
885:20445084
834:12223485
793:16511561
736:13678586
695:11953314
646:23227013
638:11679632
595:10206645
559:26280335
479:See also
398:Function
326:homologs
207:protease
171:RCSB PDB
91:InterPro
2627:Biology
2581:Ligases
2351:Enzymes
1955:Arginyl
1950:Alanine
1858:3331683
1809:3254787
1638:4134323
1589:1458989
1363:2936959
1191:1201533
1065:4349251
1012:1103709
876:2906861
784:1422162
744:7265454
618:Science
603:4346474
550:4568306
469:amyloid
318:genetic
236:called
234:peptide
120:[ 5fn5[
84:PF05450
43:(red),
2653:EC 3.4
2613:Portal
2555:Lyases
2300:3.4.99
2216:3.4.21
2139:3.4.17
2109:3.4.16
2091:3.4.15
2044:3.4.14
2009:3.4.13
1970:Leucyl
1937:3.4.11
1924:3.4.11
1865:
1855:
1816:
1806:
1768:
1727:
1686:
1645:
1635:
1617:Nature
1596:
1586:
1545:
1510:
1469:
1428:
1370:
1360:
1342:Nature
1321:
1280:
1239:
1198:
1188:
1147:
1106:
1098:
1063:
1055:
1037:Nature
1019:
1009:
968:
933:
925:
883:
873:
832:
791:
781:
763:EMBO J
742:
734:
693:
686:125968
683:
665:EMBO J
644:
636:
601:
593:
575:Nature
557:
547:
529:Nature
440:proton
322:genome
242:folded
186:PDBsum
160:
150:
70:Symbol
2507:Types
2218:-25:
1926:-19:
1104:S2CID
1061:S2CID
931:S2CID
903:(PDF)
740:S2CID
642:S2CID
599:S2CID
416:water
412:Notch
370:into
357:motif
308:, an
302:CD147
298:PEN-2
294:APH-1
286:PSEN1
272:, or
258:ErbB4
254:Notch
53:APH-1
49:PEN-2
2599:list
2592:EC7
2586:list
2579:EC6
2573:list
2566:EC5
2560:list
2553:EC4
2547:list
2540:EC3
2534:list
2527:EC2
2521:list
2514:EC1
1917:3.4)
1863:PMID
1814:PMID
1766:PMID
1725:PMID
1684:PMID
1643:PMID
1594:PMID
1543:PMID
1508:PMID
1467:PMID
1426:PMID
1368:PMID
1319:PMID
1278:PMID
1237:PMID
1196:PMID
1145:PMID
1096:PMID
1053:PMID
1017:PMID
966:PMID
923:PMID
881:PMID
830:PMID
789:PMID
732:PMID
714:Cell
691:PMID
634:PMID
591:PMID
555:PMID
344:and
274:CD44
179:PDBj
175:PDBe
158:ECOD
148:Pfam
79:Pfam
1853:PMC
1845:doi
1804:PMC
1796:doi
1756:doi
1752:100
1715:doi
1674:doi
1633:PMC
1625:doi
1621:512
1584:PMC
1574:doi
1570:103
1535:doi
1498:doi
1494:279
1457:doi
1453:279
1416:doi
1412:280
1358:PMC
1350:doi
1346:467
1309:doi
1305:279
1268:doi
1264:279
1227:doi
1223:280
1186:PMC
1176:doi
1172:280
1135:doi
1131:279
1088:doi
1045:doi
1041:440
1007:PMC
997:doi
993:102
958:doi
915:doi
871:PMC
861:doi
857:107
820:doi
816:277
779:PMC
771:doi
722:doi
718:114
681:PMC
673:doi
626:doi
622:294
583:doi
579:398
545:PMC
537:doi
533:525
166:PDB
132:155
108:244
2639::
2164:A2
2127:DD
2119::
1915:EC
1909::
1861:.
1851:.
1839:.
1835:.
1812:.
1802:.
1790:.
1778:^
1764:.
1750:.
1746:.
1723:.
1711:13
1709:.
1705:.
1682:.
1670:94
1668:.
1664:.
1641:.
1631:.
1619:.
1615:.
1592:.
1582:.
1568:.
1564:.
1541:.
1531:45
1529:.
1506:.
1492:.
1488:.
1465:.
1451:.
1447:.
1424:.
1410:.
1406:.
1385:.
1366:.
1356:.
1344:.
1340:.
1317:.
1303:.
1299:.
1276:.
1262:.
1258:.
1235:.
1221:.
1217:.
1194:.
1184:.
1170:.
1166:.
1143:.
1129:.
1125:.
1102:.
1094:.
1084:69
1082:.
1059:.
1051:.
1039:.
1015:.
1005:.
991:.
987:.
964:.
954:19
952:.
929:.
921:.
909:.
905:.
879:.
869:.
855:.
851:.
828:.
814:.
810:.
787:.
777:.
767:25
765:.
761:.
738:.
730:.
716:.
712:.
689:.
679:.
669:21
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663:.
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