Proton Transport in Mitochondrial UCP2 is Regulated by a Matrix-Oriented Salt-Bridge Network

Abstract

strengthen the complex. A major feature in the complex is the blockade of VDAC1's permeation pathway by HK2, a result supported by electrophysiological measurements. The HK2-VDAC1 interface is highlighted by the presence of a putative GSK3b phosphorylation site, S215, whose phosphorylation disrupts the most probable binding site of HK2 in VDAC1. Consistent with the simulation results, electrophysiological experiments show that HK2 blocks ion conduction in wildtype VDAC1 but not in the phosphomimetic S215E mutant. Furthermore, the S215E mutation reduces cell survival rate under hypoxia-reoxygenation stress, possibly due to reduced HK2 binding. Together, our results provide a novel, experimentally validated model for membrane-bound HK2-VDAC1 complex.