title: Functional dynamics in the voltage-dependent anion channel.
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 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.
authors.affiliation: Department of NMR based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Villinger
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Briones
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zachariae
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004024:Dicyclohexylcarbodiimide / Q000737:chemistry; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D017433:Protein Structure, Secondary; D012996:Solutions; D013997:Time Factors; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D008051:Lipid Bilayers; D012996:Solutions; D004024:Dicyclohexylcarbodiimide; D050995:Voltage-Dependent Anion Channel 1; D004134:Dimyristoylphosphatidylcholine