Mapping the N-Terminal Hexokinase-I Binding Site onto Voltage-Dependent Anion Channel-1 To Block Peripheral Nerve Demyelination

The voltage-dependent anion channel (VDAC), the most abundant protein on the outer mitochondrial membrane, is implicated in ATP, ion and metabolite exchange with cell compartments. In particular, the VDAC participates in cytoplasmic and mitochondrial Ca2+ homeostasis. Notably, the Ca2+ efflux out of Schwann cell mitochondria is involved in peripheral nerve demyelination that underlies most peripheral neuropathies. Hexokinase (HK) isoforms I and II, the main ligands of the VDAC, possess a hydrophobic N-terminal structured in alpha-helix (NHKI) that is necessary for the binding to the VDAC. To gain further insight into the molecular basis of HK binding to the VDAC, we developed and optimized peptides based on the NHKI sequence. These modifications lead to an increase of the peptide hydrophobicity and helical content that enhanced their ability to prevent peripheral nerve demyelination. Our results provide new insights into the molecular basis of VDAC/HK interaction that could lead to the development of therapeutic compounds for demyelinating peripheral neuropathies.

Automated summary

This study investigates the binding mechanism of VDAC, the most abundant protein on the outer mitochondrial membrane, to HK and enhances its ability to prevent peripheral nerve demyelination by modifying peptides. The findings provide new insights into the interaction between VDAC and HK, potentially leading to the development of therapeutic compounds for demyelinating peripheral neuropathies.