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)
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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
More general terms
Additional terms
- amyloid precursor protein; A4/beta amyloid precursor protein (APP)
- cadherin
- familial Alzheimer's disease type 4 (FAD4), AD4 locus/presenilin-2 mutation associated
Component of
References
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/7638622
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/7651536
- ↑ Alzheimer's Disase Collaborative Group Nature Genetics 11:219-222 1995
- ↑ 4.0 4.1 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
- ↑ 5.0 5.1 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
- ↑ 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
- ↑ UniProt http://www.uniprot.org/uniprot/P49810.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/PSEN2