presenilin-1; PS-1; EC=3.4.23.-; protein S182; contains: presenilin-1 NTF subunit; contains: presenilin-1 CTF subunit; contains: presenilin-1 CTF12; PS1-CTF12 (PSEN1, AD3, PS1, PSNL1)
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Function
- putative catalytic subunit of APP-gamma-secretase
- PS1 colocalizes with APP-gamma-secretase activity[12], along with nicastrin, pen-2 & APH1
- presenilins control proteolysis of APP, APLP-1 & Notch[8]
- Notch-1 is thought to be the physiologic substrate of PS1
- PS1 is first synthesized as a zymogen, then becomes active after being cleaved. (see proteolytic site {line drawing})
- p53 & p21WAF1 inhibit presenilin-1 expression & leads to apoptosis & tumor suppression[5]
- alternate cleavage forms of PS-1 & 2 by a caspase-3 family protease occurs during apoptosis[6]
- PS1 interacts (coprecipitates) with beta-catenin & gamma-catenin
- PS1 complexes with protein kinase A & GSK3 to phosphorylate beta-catenin such that it interacts with beta-TRCP & becomes ubiquinated & degraded; this is similar to the APC/axin/CSNK1A1/GSK3 complex in the wnt1 signalling pathway, however the presenilin complex is not affected by wnt1[22]
- cadherins, calsenilin, DOCK3, PARL, KCNIP4 also interact with PS1
- may play a role in intracellular signaling & 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 Ca+2 influx, cleaves E-cadherin promoting disassembly of the E-cadherin/catenin complex & increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling
- may also play a role in hematopoiesis
- heterogeneous proteolytic processing generates N-terminal (NTF) & C-terminal (CTF) fragments of approximately 35 & 20 kDa, respectively. during apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12
- after endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on Ser by PKA &/or PKC
- phosphorylation on Ser-346 inhibits endoproteolysis
- homodimer
- associates with proteolytic processed C-terminal fragments C83 & C99 of the amyloid precursor protein (APP)
- associates with NOTCH1
- component of cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2
- interaction with CDH1 stabilizes the complex & stimulates cell-cell aggregation
- interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane
- interacts with CTNND2, CTNNB1, HERPUD1, FLNA, FLNB, MTCH1, PKP4 & PARL
- interacts through its N-terminus with isoform 3 of GFAP
- interacts with DOCK3
- PS1 & PS2 have turnover times of ~15 min
- proteolytically cleaved N & C terminal fragments form heterodimers within the APP-gamma-secretase complex with a turnover time apparently > 12 hours [13-16,20]
Structure
- predominantly heterodimer of a N-terminal (NTF) & a C-terminal (CTF) endoproteolytical fragment
- two conserved transmembrane aspartates in PS1 [Asp257 in transmembrane domain 6 (TM6) & Asp385 in transmembrane domain 7 (TM7)] are required for endoproteolysis (between Thr291 & Ala299 within the cytoplasmic loop between TM6 & TM7) & 'gamma-secretase' cleavage of APP to A4[10][11]
- PS1 & PS2 appear to contain the active site of a gamma-secretase[18]
- the PAL motif is required for normal active site conformation
- belongs to the peptidase A22A family
Compartment
- localized to the endoplasmic reticulum & pre-GOLGI[19]
- may also be associated with the plasma membrane[20]
- bound to NOTCH1 also at the cell surface
- colocalizes with CDH1/2 at sites of cell-cell contact
- colocalizes with CTNNB1 in the endoplasmic reticulum & the proximity of the plasma membrane
- also present in azurophil granules of neutrophils
Alternative splicing
named isoforms=6 some isoforms may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay
Pathology
- missense mutations in PS1 associated with:
- early onset Alzheimer's disease
- mutations in PS1 affect APP-gamma secretase activity
- PS1 mutations also affect APP beta-secretase activity[17]
- deficiency of presenilin-1 inhibits transmembrane domain APP cleavage by gamma-secretase with accumulation of carboxy-terminal portion of APP & drop in production of A4 peptide[7]
- one of 3 components of APP gamma-secretase complex in which haploinsufficiency is associated with hidradenitis suppurativa
Genetics
- protein product of autosomal dominant gene on 14q24.3
- PS1 knockout mice are not viable
Laboratory
More general terms
Additional terms
- Alzheimer's disease (AD)
- amyloid precursor protein; A4/beta amyloid precursor protein (APP)
- notch (Drosophila) homolog protein
- presenilin 1 (PSEN1) genetic mutation analysis
- presenilin-1 (PS-1) knockout mouse
Component of
References
- ↑ Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7596406
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/7550356
- ↑ Murphy GM Jr, Forno LS, Ellis WG, Nochlin D, Levy-Lahad E, Poorkaj P, Bird TD, Jiang Z, Cordell B. Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease. Am J Pathol. 1996 Dec;149(6):1839-46. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8952521
- ↑ Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995 Sep 28;377(6547):351-4. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7566091
- ↑ 5.0 5.1 Roperch JP, Alvaro V, Prieur S, Tuynder M, Nemani M, Lethrosne F, Piouffre L, Gendron MC, Israeli D, Dausset J, Oren M, Amson R, Telerman A. Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression. Nat Med. 1998 Jul;4(7):835-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9662377
- ↑ 6.0 6.1 Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science. 1997 Jul 18;277(5324):373-6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9219695
- ↑ 7.0 7.1 De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22;391(6665):387-90. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9450754
- ↑ 8.0 8.1 Haass C, De Strooper B. The presenilins in Alzheimer's disease-proteolysis holds the key. Science. 1999 Oct 29;286(5441):916-9. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10542139
- ↑ Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999 Jun 24;399(6738 Suppl):A23-31. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10392577
- ↑ 10.0 10.1 Kimberly WT, Xia W, Rahmati T, Wolfe MS, Selkoe DJ. The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J Biol Chem. 2000 Feb 4;275(5):3173-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10652302
- ↑ 11.0 11.1 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: https://www.ncbi.nlm.nih.gov/pubmed/10206644
- ↑ 12.0 12.1 Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, Shi XP, Yin KC, Shafer JA, Gardell SJ. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6138-43. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10801983
- ↑ Harman. J Am Aging Assoc (AGE) 23:147, 2000
- ↑ Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, Levesque L, Rogaeva E, Xu D, Liang Y, Duthie M, St George-Hyslop PH, Fraser PE. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains beta-catenin. J Biol Chem. 1998 Jun 26;273(26):16470-5. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9632714
- ↑ Jacobsen H, Reinhardt D, Brockhaus M, Bur D, Kocyba C, Kurt H, Grim MG, Baumeister R, Loetscher H. The influence of endoproteolytic processing of familial Alzheimer's disease presenilin 2 on abeta42 amyloid peptide formation. J Biol Chem. 1999 Dec 3;274(49):35233-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10575009
- ↑ Capell A, Grunberg J, Pesold B, Diehlmann A, Citron M, Nixon R, Beyreuther K, Selkoe DJ, Haass C. The proteolytic fragments of the Alzheimer's disease- associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J Biol Chem. 1998 Feb 6;273(6):3205-11. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9452432
- ↑ 17.0 17.1 Russo C, Schettini G, Saido TC, Hulette C, Lippa C, Lannfelt L, Ghetti B, Gambetti P, Tabaton M, Teller JK. Presenilin-1 mutations in Alzheimer's disease. Nature. 2000 Jun 1;405(6786):531-2. No abstract available. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10850703
- ↑ 18.0 18.1 Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000 Jun 8;405(6787):689-94. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10864326
- ↑ 19.0 19.1 Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001 Dec 6;414(6864):643-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11740561
- ↑ 20.0 20.1 Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11274343
- ↑ De Strooper B, Annaert W. Where Notch and Wnt signaling meet. The presenilin hub. J Cell Biol. 2001 Feb 19;152(4):F17-20. No abstract available. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11266476
- ↑ 22.0 22.1 Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002 Sep 20;110(6):751-62. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12297048
- ↑ UniProt http://www.uniprot.org/uniprot/P49768.html
- ↑ Alzheimer research forum; Note: presenilins mutations http://www.alzforum.org/res/com/mut/pre/default.asp
- ↑ GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/PSEN1
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5663
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5663
- OMIM: https://mirror.omim.org/entry/104311
- OMIM: https://mirror.omim.org/entry/600274
- OMIM: https://mirror.omim.org/entry/607822
- UniProt: http://www.uniprot.org/uniprot/P49768.html