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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)

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 Kinetic parameters: - 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: a) early onset Alzheimer's disease b) mutations in PS1 affect APP-gamma secretase activity c) 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: - presenilin 1 genetic mutation analysis

Related

Alzheimer's disease (AD) amyloid precursor protein (APP) or A4/beta amyloid precursor protein notch (Drosophila) homolog protein presenilin 1 (PSEN1) genetic mutation analysis presenilin-1 (PS-1) gene presenilin-1 (PS-1) knockout mouse PSEN1 gene mutation

General

presenilin transmembrane 8 protein

Properties

SIZE: entity length = 467 aa COMPARTMENT: endoplasmic reticulum golgi plasma membrane MOTIF: cytoplasmic domain {N-terminal} transmembrane domain {TM1} exoplasmic loop LOOP#: 1 transmembrane domain {TM2} cytoplasmic loop LOOP#: 1 transmembrane domain {TM3} exoplasmic loop LOOP#: 2 transmembrane domain {TM4} cytoplasmic loop LOOP#: 2 transmembrane domain {TM5} exoplasmic loop MOTIF: N-glycosylation site {exoplasmic loop [N279] } LOOP#: 3 transmembrane domain {TM6} MOTIF: aspartate residue {TM6} cytoplasmic loop MOTIF: proteolytic site {cytoplasmic loop LOOP#: 3} binding site SITE: cytoplasmic loop LOOP#: 3 FOR-BINDING-OF: catenin N-glycosylation site {N405} LOOP#: 3 transmembrane domain {TM7} MOTIF: aspartate residue {TM7} exoplasmic loop LOOP#: 4 transmembrane domain {TM8} cytoplasmic domain {C-terminal}

References

  1. 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: 7596406
  2. 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
  3. 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: 8952521
  4. 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: 7566091
  5. 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: 9662377
  6. 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: 9219695
  7. 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: 9450754
  8. 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: 10542139
  9. Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999 Jun 24;399(6738 Suppl):A23-31. Review. PMID: 10392577
  10. 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: 10652302
  11. 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
  12. 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: 10801983
  13. Harman. J Am Aging Assoc (AGE) 23:147, 2000
  14. 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: 9632714
  15. 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: 10575009
  16. 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: 9452432
  17. 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: 10850703
  18. 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: 10864326
  19. 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: 11740561
  20. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  21. 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: 11266476
  22. 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: 12297048
  23. UniProt :accession P49768
  24. Alzheimer research forum; Note: presenilins mutations http://www.alzforum.org/res/com/mut/pre/default.asp
  25. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/PSEN1

Component-of

APP gamma-secretase

Databases & Figures

OMIM correlations MORBIDMAP 104311 UniProt P49768 Pfam PF01080 Entrez Gene 5663 Kegg hsa:5663 Wnt1 signalling pathway