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]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000205155 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036835 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.