Presenilin-1

UniProt P49768 Organism Homo sapiens Gene AD3, PS1, PSEN1, PSNL1 EC 3.4.23.-

Also known as: AD3, PS1, PSEN1, PSNL1

Function

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 (amyloid-beta precursor protein). Requires the presence of the other members of the gamma-secretase complex for protease activity. Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels. Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin). Under conditions of apoptosis or calcium influx, cleaves CDH1. This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling. Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis. Involved in the regulation of neurite outgrowth. Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).

Classification

Family (Pfam): PF01080 Presenilin
InterPro: Pept_A22A_PS1, Peptidase_A22A, Preselin/SPP, Presenilin_C
Functional cluster: Membrane Transporters & GPCRs

Experimental structures · PDB · 27

2KR6 NMR
4UIS EM 4.40A
5A63 EM 3.40A
5FN2 EM 4.20A
5FN3 EM 4.10A
5FN4 EM 4.00A
5FN5 EM 4.30A
6IDF EM 2.70A
6IYC EM 2.60A
6LQG EM 3.10A
6LR4 EM 3.00A
7C9I EM 3.10A
… and 15 more

A predicted model is available from AlphaFold.

Gene Ontology · 88

Disease associations

Pick disease MONDO:0008243
semantic dementia MONDO:0010857
Alzheimer disease 3 MONDO:0011913
dilated cardiomyopathy 1U MONDO:0013371
acne inversa, familial, 3 MONDO:0013398

Drugs targeting this protein · 7

AVAGACESTAT inhibitor
NIROGACESTAT inhibitor
TARENFLURBIL modulator
RG-4733 inhibitor
NIROGACESTAT HYDROBROMIDE inhibitor
BEGACESTAT inhibitor
SEMAGACESTAT inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Presenilin-2 14 shared papers
Nicastrin 9 shared papers
Gamma-secretase subunit PEN-2 8 shared papers
Gamma-secretase subunit APH-1A 7 shared papers
Mitochondrial carrier homolog 1 1 shared papers
Presenilin-1 4 shared papers
Protein crumbs homolog 2 1 shared papers
Presenilin-1 1 shared papers
Presenilin-2 1 shared papers
Presenilin-1 1 shared papers
Presenilin-2 1 shared papers
Delta-like protein 3 1 shared papers

Literature · 139 cited papers

Recognition of the amyloid precursor protein by human gamma-secretase. Science · 2019
Structural basis of Notch recognition by human gamma-secretase. Nature · 2019
PSEN1 p.Thr116Ile variant in two Korean families with young onset Alzheimer's disease. Int. J. Mol. Sci. · 2018
Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset Alzheimer's disease with parkinsonism. Neurobiol. Aging · 2018
Phenotypic variability in autosomal dominant familial Alzheimer disease due to the S170F mutation of presenilin-1. Neurodegener. Dis. · 2018
Neuropathology and biochemistry of early onset familial Alzheimer's disease caused by presenilin-1 missense mutation Thr116Asn. J. Neural Transm. · 2018
Genetic screening in two Iranian families with early-onset Alzheimer's disease identified a novel PSEN1 mutation. Neurobiol. Aging · 2018
A novel PSEN1 K311R mutation discovered in Chinese families with late-onset Alzheimer's disease affects amyloid-beta production and tau phosphorylation. J. Alzheimers Dis. · 2017
Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc. Natl. Acad. Sci. U.S.A. · 2017
The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida. Am. J. Neurodegener. Dis. · 2016
Sampling the conformational space of the catalytic subunit of human gamma-secretase. Elife · 2015
Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-onset Alzheimer's disease. Neurosci. Lett. · 2016
… and 127 more in the literature graph

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