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presenilin-2; PS-2; STM-2; E5-1; AD3LP; AD5; contains: presenilin-2 NTF subunit; contains: presenilin-2 CTF subunit (PSEN2, AD4, PS2, PSNL2, STM2)

Function: - presumptive aspartic proteinase & catalytic subunit of APP gamma secretase or related complex, that may include cadherins[5] - may play a role in intracellular signaling & gene expression or in linking chromatin to the nuclear membrane - may function in the cytoplasmic partitioning of proteins - heterogeneous proteolytic processing generates N-terminal and - C-terminal fragments - phosphorylated on Ser - interacts with DOCK3 (putative). - interacts with HERPUD1, FLNA, FLNB & PARL Kinetic parameters - PS-1 & PS-2 have turnover times of ~15 min, - proteolytically cleaved N & C terminal fragments form a heterodimers, a 100-150 kD molecular complex with a turnover time of > 12 hours [5-9] Structure: - homodimer - the PAL motif is required for normal active site conformation (putative) - belongs to the peptidase A22A family Compartment: - PS1 & PS2 are associated with membranes of the secretory, but may also be associated with the plasma membrane [5] - endoplasmic reticulum membrane - Golgi membrane Alternative splicing: named isoforms=2; Alternate cleavage forms of PS-1 & 2 by a caspase-3 family protease occurs during apoptosis [4] Expression: - isoform 1 is seen in the placenta, skeletal muscle & heart - isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle & kidney Pathology: - protein product of autosomal dominant gene on 1q31-42 bearing point mutation resulting in ~1.2-3x increase production of A-beta 42 & giving rise to early onset Alzheimer's disease

Related

amyloid precursor protein (APP) or A4/beta amyloid precursor protein cadherin familial Alzheimer's disease type 4 (FAD4), AD4 locus/presenilin-2 mutation associated presenilin-2 (PS-2) gene (E5-1, STM2, ALG-3 {mouse homolog}) PSEN2 gene mutation

General

presenilin transmembrane 8 protein

Properties

SIZE: entity length = 448 aa COMPARTMENT: endoplasmic reticulum golgi plasma membrane MOTIF: transmembrane domain {TM1} transmembrane domain {TM2} transmembrane domain {TM3} transmembrane domain {TM4} transmembrane domain {TM5} transmembrane domain {TM6} MOTIF: aspartate residue {TM6} transmembrane domain {TM7} transmembrane domain {TM8} cytoplasmic domain {N-TERMINAL} exoplasmic loop LOOP#: 1 exoplasmic loop LOOP#: 2 exoplasmic loop LOOP#: 3 exoplasmic loop LOOP#: 4 cytoplasmic domain {N-terminal} cytoplasmic loop LOOP#: 1 cytoplasmic loop LOOP#: 2 cytoplasmic loop MOTIF: proteolytic site {cytoplasmic loop LOOP#: 3} N-glycosylation site {N386} LOOP#: 3 cytoplasmic domain {C-terminal} cytoplasmic domain {C-TERMINAL}

Database Correlations

OMIM correlations MORBIDMAP 600759 UniProt P49810 Pfam PF01080 Entrez Gene 5664 Kegg hsa:5664

References

  1. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973-7. PMID: 7638622
  2. 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
  3. Alzheimer's Disase Collaborative Group Nature Genetics 11:219-222 1995
  4. 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
  5. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: 11274343
  6. Harman. J Am Aging Assoc (AGE) 23:147, 2000
  7. 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
  8. 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
  9. 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
  10. UniProt :accession P49810
  11. Alzheimer research forum; Note: presenilins mutations http://www.alzforum.org/res/com/mut/pre/default.asp
  12. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/PSEN2