PSENEN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPSENEN, MSTP064, PEN-2, PEN2, MDS033, presenilin enhancer gamma-secretase subunit, ACNINV2, presenilin enhancer, gamma-secretase subunit
External IDsOMIM: 607632 MGI: 1913590 HomoloGene: 11952 GeneCards: PSENEN
Orthologs
SpeciesHumanMouse
Entrez

55851

66340

Ensembl

ENSG00000205155

ENSMUSG00000036835

UniProt

Q9NZ42

Q9CQR7

RefSeq (mRNA)

NM_172341
NM_001281532
NM_018468

NM_025498
NM_001364016
NM_001364017

RefSeq (protein)

NP_001268461
NP_758844

NP_079774
NP_001350945
NP_001350946

Location (UCSC)Chr 19: 35.75 – 35.75 MbChr 7: 30.26 – 30.26 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PSENEN, formally PEN-2 (presenilin enhancer 2), is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin.[5] PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment.[6] Biochemical studies have shown that a conserved sequence motif D-Y-L-S-F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex.[7]

PEN-2 binds to metformin at therapeutic concentration and may be responsible for its AMPK-activating effects. PEN2-metformin in turn binds to ATP6AP1 to inhibit v-ATPase activity.[8]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000205155 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036835 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Kaether C, Haass C, Steiner H (2006). "Assembly, trafficking and function of gamma-secretase". Neuro-Degenerative Diseases. 3 (4–5): 275–283. doi:10.1159/000095267. PMID 17047368. S2CID 17324271.
  6. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, et al. (July 2002). "aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation". Developmental Cell. 3 (1): 85–97. doi:10.1016/S1534-5807(02)00189-2. PMID 12110170.
  7. Hasegawa H, Sanjo N, Chen F, Gu YJ, Shier C, Petit A, et al. (November 2004). "Both the sequence and length of the C terminus of PEN-2 are critical for intermolecular interactions and function of presenilin complexes". The Journal of Biological Chemistry. 279 (45): 46455–46463. doi:10.1074/jbc.M406289200. PMID 15322109.
  8. Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, et al. (March 2022). "Low-dose metformin targets the lysosomal AMPK pathway through PEN2". Nature. 603 (7899): 159–165. Bibcode:2022Natur.603..159M. doi:10.1038/s41586-022-04431-8. PMC 8891018. PMID 35197629.
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