Functional dynamics in the voltage-dependent anion channel

Saskia Villinger, Rodolfo Briones, Karin Giller, Ulrich Zachariae, Adam Lange, Bert L. de Groot, Christian Griesinger, Stefan Becker, Markus Zweckstetter

Research output: Contribution to journalArticlepeer-review

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 beta-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.

Original languageEnglish
Pages (from-to)22546-22551
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume107
Issue number52
DOIs
Publication statusPublished - 28 Dec 2010

Keywords

  • membrane protein
  • molecular dynamics
  • NMR spectroscopy
  • protein-lipid interactions
  • structure
  • CHARACTERIZING CHEMICAL-EXCHANGE
  • MITOCHONDRIAL OUTER MEMBRANES
  • APOPTOTIC CELL-DEATH
  • TRANSMEMBRANE DOMAIN
  • MECHANISTIC INSIGHTS
  • SELECTIVE CHANNEL
  • ESCHERICHIA-COLI
  • NMR-SPECTROSCOPY
  • SINGLE-PARAMETER
  • PROTEIN

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