Gamma-secretase subunit PEN-2

UniProt Q9NZ42 Organism Homo sapiens Gene PEN2, PSENEN

Also known as: PEN2, PSENEN

Function

Essential 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). The gamma-secretase complex 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 (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity. Besides its role in gamma-secretase complex, acts as a regulator of AMP-activated protein kinase (AMPK) activity in response to calorie restriction: binds metformin, an antidiabetic drug, promoting association with ATP6AP1, a subunit of the V-ATPase complex, leading to V-ATPase complex inhibition on lysosomes and AMPK activation via the AXIN1-STK11/LKB1 axis (By similarity).

Classification

Family (Pfam): PF10251 PEN-2
InterPro: Gamma_Secretase_Asp_P_PEN2
Functional cluster: Photosystem II Reaction-Center & Antimicrobial Peptides

Experimental structures · PDB · 27

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
7D8X EM 2.60A
7Y5T EM 2.90A
… and 15 more

A predicted model is available from AlphaFold.

Gene Ontology · 21

Disease associations

acne inversa, familial, 2 MONDO:0013397

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

Gamma-secretase subunit APH-1A 10 shared papers
Gamma-secretase subunit PEN-2 2 shared papers
Nicastrin 8 shared papers
Presenilin-1 8 shared papers
Gamma-secretase subunit APH-1B 1 shared papers
Gamma-secretase subunit PEN-2 1 shared papers
Gamma-secretase subunit pen-2 1 shared papers
Gamma-secretase subunit Aph-1b 1 shared papers
Gamma-secretase subunit aph-1 1 shared papers
Gamma-secretase subunit pen-2 1 shared papers
Gamma-secretase subunit Aph-1 1 shared papers
Neurogenic locus notch homolog protein 1 1 shared papers

Literature · 16 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
Sampling the conformational space of the catalytic subunit of human gamma-secretase. Elife · 2015
An atomic structure of human gamma-secretase. Nature · 2015
Three-dimensional structure of human gamma-secretase. Nature · 2014
Pen-2 is essential for gamma-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry · 2014
Gamma-secretase gene mutations in familial acne inversa. Science · 2010
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat. Genet. · 2004
APH1, PEN2, and nicastrin increase Abeta levels and gamma-secretase activity. Biochem. Biophys. Res. Commun. · 2003
Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl. Acad. Sci. U.S.A. · 2003
Reconstitution of gamma-secretase activity. Nat. Cell Biol. · 2003
… and 4 more in the literature graph

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