Functional dynamics in the voltage-dependent anion channel

S. Villinger, R. Briones, K. Giller, Ulrich Zachariae, A. Lange, B.L. De Groot, C. Griesinger, S. Becker, M. Zweckstetter

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    77 Citations (Scopus)

    Abstract

    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 ß-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 microto millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.
    Original languageEnglish
    Pages (from-to)22546-22551
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number52
    DOIs
    Publication statusPublished - 28 Dec 2010

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