Presenilin enhancer protein 2 (PEN2) (PEN2)

Presenilin enhancer protein 2 (PEN2) is a critical 101-amino acid transmembrane subunit of the gamma-secretase complex, which is responsible for the intramembrane proteolysis of proteins such as the amyloid precursor protein (APP) and Notch (UniProt P0C0L5). While traditionally studied for its role in Alzheimer's disease, recent research has identified PEN2 as a primary lysosomal receptor for the widely used anti-diabetic drug metformin (Ma et al., Nature, 2022). Upon binding metformin, PEN2 undergoes a conformational change that enables it to interact with the v-ATPase subunit ATP6V1A, effectively inhibiting v-ATPase activity and triggering the activation of AMP-activated protein kinase (AMPK) via a lysosomal-dependent mechanism (Ma et al., Nature, 2022; Zhang et al., Nature, 2017). This pathway is essential for metformin's glucose-lowering effects and its potential anti-aging properties. Additionally, mutations in the PSENEN gene encoding PEN2 are associated with familial Alzheimer's disease and skin disorders like acne inversa and Dowling-Degos disease (PubMed: 22424607).

Other names

PSENENGamma-secretase subunit PEN-2Presenilin enhancer 2MSTP064

Metformin binds directly to the PEN2 subunit, which then facilitates an interaction with the v-ATPase subunit ATP6V1A, leading to the inhibition of v-ATPase and the subsequent activation of the lysosomal AMPK pathway (Ma et al., Nature, 2022).