Nucleotide Interactions of the Human Voltage-dependent Anion Channel

作者：Villinger Saskia; Giller Karin; Bayrhuber Monika; Lange Adam; Griesinger Christian; Becker Stefan; Zweckstetter Markus^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(19): 13397-13406.

DOI：10.1074/jbc.M113.524173

• ATP
• Membrane Proteins
• NMR
• Nucleotide
• Organic Anion Channels
• Interactions

Background: Human VDAC1 mediates and controls the transport of metabolites across the outer mitochondrial membrane. Results: The N-terminal helix of hVDAC1 is involved in binding to charged forms of ATP, UTP, and GTP with an important contribution from lysine 20. Conclusion: Weak binding of ATP confers specificity for ATP transport. Significance: ATP interaction mapped at residue resolution supports metabolite selectivity of VDAC.
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 -helix, the linker connecting the helix to the first -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 Mg2+-complexed ATP form is possible.

• 出版日期2014-5-9