title: Molecular Plasticity of the Human Voltage-Dependent Anion Channel Embedded Into a Membrane.
abstract: The voltage-dependent anion channel (VDAC) regulates the flux of metabolites and ions across the outer mitochondrial membrane. Regulation of ion flow involves conformational transitions in VDAC, but the nature of these changes has not been resolved to date. By combining single-molecule force spectroscopy with nuclear magnetic resonance spectroscopy we show that the β barrel of human VDAC embedded into a membrane is highly flexible. Its mechanical flexibility exceeds by up to one order of magnitude that determined for β strands of other membrane proteins and is largest in the N-terminal part of the β barrel. Interaction with Ca(2+), a key regulator of metabolism and apoptosis, considerably decreases the barrel's conformational variability and kinetic free energy in the membrane. The combined data suggest that physiological VDAC function depends on the molecular plasticity of its channel.
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zürich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Lin
authors.initials: L
authors.lastname: Ge
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.affiliation: Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zürich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Stefania A
authors.initials: SA
authors.lastname: Mari
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zürich, Mattenstrasse 26, 4058 Basel, Switzerland. Electronic address: daniel.mueller@bsse.ethz.ch.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany; Structural Biology in Dementia, German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Strasse 3a, 37075 Göttingen, Germany; Department of Neurology, University Medical Center Göttingen, University of Göttingen, Am Waldweg 33, 37073 Göttingen, Germany. Electronic address: markus.zweckstetter@dzne.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D002118:Calcium / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051336:Mitochondrial Membranes / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D000072760:Single Molecule Imaging; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; D002118:Calcium
keywords: NMR spectroscopy; atomic force microscopy; calcium dependency; conformational variability; human voltage-dependent anion channel; integral membrane protein; single-molecule force spectroscopy; structural flexibility