title: Nucleotide interactions of the human voltage-dependent anion channel.
abstract: The voltage-dependent anion channel (VDAC) mediates and gates the flux of metabolites and ions across the outer mitochondrial membrane and is a key player in cellular metabolism and apoptosis. Here we characterized the binding of nucleotides to human VDAC1 (hVDAC1) on a single-residue level using NMR spectroscopy and site-directed mutagenesis. We find that hVDAC1 possesses one major binding region for ATP, UTP, and GTP that partially overlaps with a previously determined NADH binding site. This nucleotide binding region is formed by the N-terminal α-helix, the linker connecting the helix to the first β-strand and adjacent barrel residues. hVDAC1 preferentially binds the charged forms of ATP, providing support for a mechanism of metabolite transport in which direct binding to the charged form exerts selectivity while at the same time permeation of the Mg(2+)-complexed ATP form is possible.
authors.affiliation: From the 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: Karin
authors.initials: K
authors.lastname: Giller
authors.forename: Monika
authors.initials: M
authors.lastname: Bayrhuber
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
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: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology; D006160:Guanosine Triphosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009243:NAD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D014544:Uridine Triphosphate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C494762:VDAC1 protein, human; D009243:NAD; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D050995:Voltage-Dependent Anion Channel 1; D014544:Uridine Triphosphate
keywords: ATP; Interactions; Membrane Proteins; NMR; Nucleotide; Organic Anion Channels