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

Autor: Gautier B; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France., Forêt Jacquard M; UAR CNRS 3278, Centre de Recherche Insulaire et Observatoire de l'Environnement (CRIOBE), CNRS-EPHE-UPVD, Université de Perpignan Via Domitia, bâtiment T, 58 avenue P. Alduy, Perpignan 66860, France., Guelfi S; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France., Abbou S; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France., Gonzalez E; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France., Berthelot J; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France., Boukhaddaoui H; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France., Lebrun A; LMP, University of Montpellier, Montpellier 34095, France., Legrand B; Institut des Biomolécules Max Mousseron, IBMM, UMR 5247, CNRS, Université de Montpellier, ENSCM, 15 Avenue Charles Flahault, Montpellier 34093, France., Tricaud N; Institut des Neurosciences de Montpellier, Université de Montpellier, 80 rue A. Fliche, Montpellier 34091, France.; LMP, University of Montpellier, Montpellier 34095, France.; I-Stem, UEVE U861, INSERM U861, AFM, Corbeil-Essonnes 91100, France., Inguimbert N; UAR CNRS 3278, Centre de Recherche Insulaire et Observatoire de l'Environnement (CRIOBE), CNRS-EPHE-UPVD, Université de Perpignan Via Domitia, bâtiment T, 58 avenue P. Alduy, Perpignan 66860, France.; LMP, University of Montpellier, Montpellier 34095, France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Sep 08; Vol. 65 (17), pp. 11633-11647. Date of Electronic Publication: 2022 Aug 19.
DOI: 10.1021/acs.jmedchem.2c00411
Abstrakt: 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 Ca 2+ homeostasis. Notably, the Ca 2+ 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 α-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.
Databáze: MEDLINE
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