Functional dynamics in the voltage-dependent anion channel

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-12, Vol.107 (52), p.22546-22551
• Main Authors: Villinger, Saskia, Briones, Rodolfo, Giller, Karin, Zachariae, Ulrich, Lange, Adam, de Groot, Bert L., Griesinger, Christian, Becker, Stefan, Zweckstetter, Markus, Gouaux, Eric
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Apoptosis; Biological Sciences; Cells; Crystal structure; Crystallography, X-Ray; Dicyclohexylcarbodiimide - chemistry; Dimyristoylphosphatidylcholine - chemistry; Humans; Ion Channel Gating - physiology; Ions; Kinetics; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lipids; Magnetic Resonance Spectroscopy - methods; Membrane proteins; Membranes; Mice; Mitochondrial Membranes - chemistry; Mitochondrial Membranes - metabolism; Modeling; Models, Molecular; Molecular Dynamics Simulation; Molecular structure; Mutation, Missense; NMR; Nuclear magnetic resonance; P branes; Principal components analysis; Protein Structure, Secondary; Proteins; Simulation; Solutions; Spectroscopy; Spectrum analysis; Time Factors; Voltage dependent anion channels; Voltage-Dependent Anion Channel 1 - chemistry; Voltage-Dependent Anion Channel 1 - genetics; Voltage-Dependent Anion Channel 1 - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1012310108

The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites. Here we reveal functional dynamics of isoform one of VDAC (VDAC1) by a combination of solution NMR spectroscopy, Gaussian network model analysis, and molecular dynamics simulation. Micro- to millisecond dynamics are significantly increased for the N-terminal six β-strands of VDAC1 in micellar solution, in agreement with increased B-factors observed in the same region in the bicellar crystal structure of VDAC1. Molecular dynamics simulations reveal that a charge on the membrane-facing glutamic acid 73 (E73) accounts for the elevation of N-terminal protein dynamics as well as a thinning of the nearby membrane. Mutation or chemical modification of E73 strongly reduces the micro- to millisecond dynamics in solution. Because E73 is necessary for hexokinase-I-induced VDAC channel closure and inhibition of apoptosis, our results imply that micro- to millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.