β-Barrel mobility underlies closure of the voltage-dependent anion channel

Ulrich Zachariae, Robert Schneider, Rodolfo Briones, Zrinka Gattin, Jean-Phillipe Demers, Karin Giller, Elke Maier, Markus Zweckstetter, C. Griesinger, Stefan Becker, Roland Benz, Bert L. De Groot, Adam Lange

    Research output: Contribution to journalArticlepeer-review

    83 Citations (Scopus)

    Abstract

    The voltage-dependent anion channel (VDAC) is the major protein in the outer mitochondrial membrane, where it mediates transport of ATP and ADP. Changes in its permeability, induced by voltage or apoptosis-related proteins, have been implicated in apoptotic pathways. The three-dimensional structure of VDAC has recently been determined as a 19-stranded ß-barrel with an in-lying N-terminal helix. However, its gating mechanism is still unclear. Using solid-state NMR spectroscopy, molecular dynamics simulations, and electrophysiology, we show that deletion of the rigid N-terminal helix sharply increases overall motion in VDAC's ß-barrel, resulting in elliptic, semicollapsed barrel shapes. These states quantitatively reproduce conductance and selectivity of the closed VDAC conformation. Mutation of the N-terminal helix leads to a phenotype intermediate to the open and closed states. These data suggest that the N-terminal helix controls entry into elliptic ß-barrel states which underlie VDAC closure. Our results also indicate that ß-barrel channels are intrinsically flexible.
    Original languageEnglish
    Pages (from-to)1540-1549
    Number of pages10
    JournalStructure
    Volume20
    Issue number9
    DOIs
    Publication statusPublished - 2012

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