title: β-Barrel mobility underlies closure of the voltage-dependent anion channel.
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 β-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 β-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 β-barrel states which underlie VDAC closure. Our results also indicate that β-barrel channels are intrinsically flexible.
authors: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors: Ulrich
authors: U
authors: Zachariae
authors: Robert
authors: R
authors: Schneider
authors: Rodolfo
authors: R
authors: Briones
authors: Zrinka
authors: Z
authors: Gattin
authors: Jean-Philippe
authors: JP
authors: Demers
authors: Karin
authors: K
authors: Giller
authors: Elke
authors: E
authors: Maier
authors: Markus
authors: M
authors: Zweckstetter
authors: Christian
authors: C
authors: Griesinger
authors: Stefan
authors: S
authors: Becker
authors: Roland
authors: R
authors: Benz
authors: Bert L
authors: BL
authors: de Groot
authors: Adam
authors: A
authors: Lange
mesh_terms: D019943:Amino Acid Substitution; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D004553:Electric Conductivity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000235:genetics
chemical_list: D008051:Lipid Bilayers; D008081:Liposomes; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; D004134:Dimyristoylphosphatidylcholine