PEN-2 explained

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.^[1] 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.^[2] 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.^[3]

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.^[4]

References

1. Kaether C, Haass C, Steiner H . Assembly, trafficking and function of gamma-secretase . Neuro-Degenerative Diseases . 3 . 4–5 . 275–283 . 2006 . 17047368 . 10.1159/000095267 . 17324271 .
2. Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D . 6 . 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 . July 2002 . 12110170 . 10.1016/S1534-5807(02)00189-2 . free .
3. Hasegawa H, Sanjo N, Chen F, Gu YJ, Shier C, Petit A, Kawarai T, Katayama T, Schmidt SD, Mathews PM, Schmitt-Ulms G, Fraser PE, St George-Hyslop P . 6 . 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 . November 2004 . 15322109 . 10.1074/jbc.M406289200 . free .
4. Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, Wu J, Wei X, Qu Q, Yu Y, Long S, Feng JW, Li C, Zhang C, Xie C, Wu Y, Xu Z, Chen J, Yu Y, Huang X, He Y, Yao L, Zhang L, Zhu M, Wang W, Wang ZC, Zhang M, Bao Y, Jia W, Lin SY, Ye Z, Piao HL, Deng X, Zhang CS, Lin SC . 6 . Low-dose metformin targets the lysosomal AMPK pathway through PEN2 . Nature . 603 . 7899 . 159–165 . March 2022 . 35197629 . 10.1038/s41586-022-04431-8 . 8891018 . 2022Natur.603..159M . free .