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

Ngo, Van A.; Queralt-Martín, María; Khan, Farha; Bergdoll, Lucie; Abramson, Jeff; Bezrukov, Sergey M.; Rostovtseva, Tatiana K.; Hoogerheide, David P.; Noskov, Sergei Yu.

doi:10.1021/jacs.2c03316

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

Journal Article · 03 August 2022 · Journal of the American Chemical Society

DOI: https://doi.org/10.1021/jacs.2c03316 · OSTI ID:1881077

^[1]; Queralt-Martín, María ^[2]; Khan, Farha ^[3]; Bergdoll, Lucie ^[4]; Abramson, Jeff ^[3];

^[5]; Rostovtseva, Tatiana K. ^[5];

^[6];

^[7]

Univ. of Calgary, AB (Canada); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
National Institutes of Health (NIH), Bethesda, MD (United States); Universitat Jaume I, Castelló (Spain)
Univ. of California, Los Angeles, CA (United States)
Aix-Marseille Univ., Marseille (France)
National Institutes of Health (NIH), Bethesda, MD (United States)
National Inst. of Standards and Technology (NIST), Gaithersburg, MD (United States). Center for Neutron Research
Univ. of Calgary, AB (Canada)

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 “gating,” i.e. transitioning to one of a variety of low-conducting states of unknown structure. The gated state results in nearly complete suppression of multivalent mitochondrial metabolite (such as ATP and ADP) transport, while enhancing calcium transport. Voltage gating is a universal property of β-barrel channels, but VDAC gating is anomalously sensitive to transmembrane potential. Here, we show that a single residue in the pore interior, K12, is responsible for most of VDAC’s voltage sensitivity. Using the analysis of over 40 μs of atomistic molecular dynamics (MD) simulations, we explore correlations between motions of charged residues inside the VDAC pore and geometric deformations of the β-barrel. Residue K12 is bistable; its motions between two widely separated positions along the pore axis enhance the fluctuations of the β-barrel and augment the likelihood of gating. Single channel electrophysiology of various K12 mutants reveals a dramatic reduction of the voltage-induced gating transitions. The crystal structure of the K12E mutant at a resolution of 2.6 Å indicates a similar architecture of the K12E mutant to the wild type; however, 60 μs of atomistic MD simulations using the K12E mutant show restricted motion of residue 12, due to enhanced connectivity with neighboring residues, and diminished amplitude of barrel motions. We conclude that β-barrel fluctuations, governed particularly by residue K12, drive VDAC gating transitions.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: National Institutes of Health; USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1881077

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 32 Vol. 144; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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

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