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The Single Residue K12 Governs the Exceptional Voltage Sensitivity of Mitochondrial Voltage-Dependent Anion Channel Gating



Van Ngo, Maria Queralt-Martin, Farha Khan, Lucie Bergdoll, Jeff Abramson, Sergey M. Bezrukov, Tatiana Rostovtseva, David Hoogerheide, Sergei Noskov


The voltage-dependent anion channel (VDAC) is a β-barrel channel of the mitochondrial outer membrane (MOM) that passively transports ions, metabolites, polypeptides, and single-stranded DNA. VDAC responds to a transmembrane potential by transitioning to a structurally uncharacterized low-conducting state that results in nearly complete suppression of multivalent mitochondrial metabolite (such as ATP and ADP) transport, while enhancing calcium transport. Here, using the analysis of over 50 µs of atomistic molecular dynamics (MD) simulations, we show that conductance modulations in VDAC involve the entire protein molecule. Specifically, motions of charged residues inside the VDAC pore are correlated to geometric deformations of the β-barrel, suggesting a role for both the distribution of charged residues and the pore cross-section in determining the channel conductance. Brownian dynamics simulations identified K12, whose position exhibits large fluctuations along the pore axis, as the primary residue responsible for modulating the pore conductance. Additionally, single channel electrophysiology of various K12 mutants shows dramatic reduction of the voltage-induced "gating" transitions. To reveal any structural basis of the altered gating, we resolved the crystal structure of the K12E mutant at a resolution of 2.6 Å. The architecture of the K12E mutant is similar to the wild type; however, MD simulations using the K12E structure show restricted motion of the mutated residue 12, due to enhanced connectivity with neighboring residues, and, as a result, diminished amplitude of barrel motions. We conclude that gating kinetics are controlled by charged residues in the VDAC lumen due to their mechanical coupling to the barrel dynamics.
Journal of the American Chemical Society


MD simulations, x-ray crystallography, single-channel electrophysiology, voltage gating, Brownian Dynamics


Ngo, V. , Queralt-Martin, M. , Khan, F. , Bergdoll, L. , Abramson, J. , Bezrukov, S. , Rostovtseva, T. , Hoogerheide, D. and Noskov, S. (2022), The Single Residue K12 Governs the Exceptional Voltage Sensitivity of Mitochondrial Voltage-Dependent Anion Channel Gating, Journal of the American Chemical Society, [online], (Accessed March 5, 2024)
Created August 17, 2022, Updated January 23, 2024