| Structural highlights
Disease
[PEN2_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [NICA_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. [PSN1_HUMAN] Defects in PSEN1 are a cause of Alzheimer disease type 3 (AD3) [MIM:607822]. AD3 is a familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [:][28] [29] [30] [31] [32] Defects in PSEN1 are a cause of frontotemporal dementia (FTD) [MIM:600274]. Defects in PSEN1 are the cause of cardiomyopathy dilated type 1U (CMD1U) [MIM:613694]. It is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[33] Defects in PSEN1 are the cause of familial acne inversa type 3 (ACNINV3) [MIM:613737]. A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.[34]
Function
[PEN2_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Probably represents the last step of maturation of gamma-secretase, facilitating endoproteolysis of presenilin and conferring gamma-secretase activity.[35] [36] [NICA_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. [APH1A_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex.[37] [38] [39] [PSN1_HUMAN] Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.[40] [41] [42] [43] [44] [45] [46] [47]
Publication Abstract from PubMed
Aberrant cleavage of Notch by gamma-secretase leads to several types of cancer, but how gamma-secretase recognizes its substrate remains unknown. Here we report the cryo-electron microscopy structure of human gamma-secretase in complex with a Notch fragment at a resolution of 2.7 A. The transmembrane helix of Notch is surrounded by three transmembrane domains of PS1, and the carboxyl-terminal beta-strand of the Notch fragment forms a beta-sheet with two substrate-induced beta-strands of PS1 on the intracellular side. Formation of the hybrid beta-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. These features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by gamma-secretase.
Structural basis of Notch recognition by human gamma-secretase.,Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y Nature. 2019 Jan;565(7738):192-197. doi: 10.1038/s41586-018-0813-8. Epub 2018 Dec, 31. PMID:30598546[48]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P, et al.. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PMID:8634711
- ↑ Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S, et al.. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PMID:8634712
- ↑ Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al.. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775-8. PMID:7651536 doi:http://dx.doi.org/10.1038/376775a0
- ↑ . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Alzheimer's Disease Collaborative Group. Nat Genet. 1995 Oct;11(2):219-22. PMID:7550356 doi:http://dx.doi.org/10.1038/ng1095-219
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- ↑ Lendon CL, Martinez A, Behrens IM, Kosik KS, Madrigal L, Norton J, Neuman R, Myers A, Busfield F, Wragg M, Arcos M, Arango Viana JC, Ossa J, Ruiz A, Goate AM, Lopera F. E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997;10(3):186-95. PMID:9298817 doi:<186::AID-HUMU2>3.0.CO;2-H 10.1002/(SICI)1098-1004(1997)10:3<186::AID-HUMU2>3.0.CO;2-H
- ↑ Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport. 1997 Apr 14;8(6):1537-42. PMID:9172170
- ↑ Ramirez-Duenas MG, Rogaeva EA, Leal CA, Lin C, Ramirez-Casillas GA, Hernandez-Romo JA, St George-Hyslop PH, Cantu JM. A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease. Ann Genet. 1998;41(3):149-53. PMID:9833068
- ↑ Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PMID:9384602
- ↑ Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11(3):216-21. PMID:9521423 doi:<216::AID-HUMU6>3.0.CO;2-F 10.1002/(SICI)1098-1004(1998)11:3<216::AID-HUMU6>3.0.CO;2-F
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- ↑ Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PMID:9719376
- ↑ Wisniewski T, Dowjat WK, Buxbaum JD, Khorkova O, Efthimiopoulos S, Kulczycki J, Lojkowska W, Wegiel J, Wisniewski HM, Frangione B. A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuroreport. 1998 Jan 26;9(2):217-21. PMID:9507958
- ↑ Taddei K, Kwok JB, Kril JJ, Halliday GM, Creasey H, Hallupp M, Fisher C, Brooks WS, Chung C, Andrews C, Masters CL, Schofield PR, Martins RN. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998 Oct 5;9(14):3335-9. PMID:9831473
- ↑ Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PMID:10441572 doi:S0002-9297(07)62317-9
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- ↑ Sugiyama N, Suzuki K, Matsumura T, Kawanishi C, Onishi H, Yamada Y, Iseki E, Kosaka K. A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Mutation in brief no. 254. Online. Hum Mutat. 1999;14(1):90. PMID:10447269 doi:<90::AID-HUMU19>3.0.CO;2-S 10.1002/(SICI)1098-1004(1999)14:1<90::AID-HUMU19>3.0.CO;2-S
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- ↑ Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001 Nov 14;286(18):2257-63. PMID:11710891
- ↑ Matsubara-Tsutsui M, Yasuda M, Yamagata H, Nomura T, Taguchi K, Kohara K, Miyoshi K, Miki T. Molecular evidence of presenilin 1 mutation in familial early onset dementia. Am J Med Genet. 2002 Apr 8;114(3):292-8. PMID:11920851
- ↑ Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, Steiner H. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. Epub 2002 Jun 4. PMID:12048239 doi:10.1073/pnas.112686799
- ↑ Bertoli Avella AM, Marcheco Teruel B, Llibre Rodriguez JJ, Gomez Viera N, Borrajero Martinez I, Severijnen EA, Joosse M, van Duijn CM, Heredero Baute L, Heutink P. A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease. Neurogenetics. 2002 Oct;4(2):97-104. PMID:12484344
- ↑ Kwok JB, Halliday GM, Brooks WS, Dolios G, Laudon H, Murayama O, Hallupp M, Badenhop RF, Vickers J, Wang R, Naslund J, Takashima A, Gandy SE, Schofield PR. Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J Biol Chem. 2003 Feb 28;278(9):6748-54. Epub 2002 Dec 19. PMID:12493737 doi:10.1074/jbc.M211827200
- ↑ Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin RP, Jakobs PM, Litt M, Hershberger RE. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24. PMID:17186461 doi:10.1086/509900
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- ↑ Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem. 2003 Mar 7;278(10):7850-4. Epub 2003 Jan 8. PMID:12522139 doi:http://dx.doi.org/10.1074/jbc.C200648200
- ↑ Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003 Jun 6;305(3):502-9. PMID:12763021
- ↑ Lee SF, Shah S, Li H, Yu C, Han W, Yu G. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J Biol Chem. 2002 Nov 22;277(47):45013-9. Epub 2002 Sep 23. PMID:12297508 doi:http://dx.doi.org/10.1074/jbc.M208164200
- ↑ Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem. 2003 Mar 7;278(10):7850-4. Epub 2003 Jan 8. PMID:12522139 doi:http://dx.doi.org/10.1074/jbc.C200648200
- ↑ Marlow L, Canet RM, Haugabook SJ, Hardy JA, Lahiri DK, Sambamurti K. APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity. Biochem Biophys Res Commun. 2003 Jun 6;305(3):502-9. PMID:12763021
- ↑ Steiner H, Romig H, Pesold B, Philipp U, Baader M, Citron M, Loetscher H, Jacobsen H, Haass C. Amyloidogenic function of the Alzheimer's disease-associated presenilin 1 in the absence of endoproteolysis. Biochemistry. 1999 Nov 2;38(44):14600-5. PMID:10545183
- ↑ Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem. 1999 Dec 17;274(51):36801-7. PMID:10593990
- ↑ Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999 Apr 8;398(6727):513-7. PMID:10206644 doi:10.1038/19077
- ↑ Berezovska O, Jack C, McLean P, Aster JC, Hicks C, Xia W, Wolfe MS, Kimberly WT, Weinmaster G, Selkoe DJ, Hyman BT. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. J Neurochem. 2000 Aug;75(2):583-93. PMID:10899933
- ↑ Kulic L, Walter J, Multhaup G, Teplow DB, Baumeister R, Romig H, Capell A, Steiner H, Haass C. Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5913-8. PMID:10811883 doi:10.1073/pnas.100049897
- ↑ Baki L, Marambaud P, Efthimiopoulos S, Georgakopoulos A, Wen P, Cui W, Shioi J, Koo E, Ozawa M, Friedrich VL Jr, Robakis NK. Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2381-6. PMID:11226248 doi:10.1073/pnas.041603398
- ↑ Wrigley JD, Nunn EJ, Nyabi O, Clarke EE, Hunt P, Nadin A, De Strooper B, Shearman MS, Beher D. Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding. J Neurochem. 2004 Sep;90(6):1312-20. PMID:15341515 doi:10.1111/j.1471-4159.2004.02596.x
- ↑ Wang J, Beher D, Nyborg AC, Shearman MS, Golde TE, Goate A. C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. J Neurochem. 2006 Jan;96(1):218-27. Epub 2005 Nov 23. PMID:16305624 doi:JNC3548
- ↑ Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, Lei J, Shi Y. Structural basis of Notch recognition by human gamma-secretase. Nature. 2019 Jan;565(7738):192-197. doi: 10.1038/s41586-018-0813-8. Epub 2018 Dec, 31. PMID:30598546 doi:http://dx.doi.org/10.1038/s41586-018-0813-8
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