Introduction
The voltage dependent anion channel (VDAC) is the primary gateway for ions and metabolites crossing the mitochondrial outer membrane. It mediates the exchange of ATP and ADP and other essential metabolites contributing to mitochondrial physiology and apoptosis regulation. The properties of VDAC like voltage gating, ion selectivity shifts and interaction with modulatory proteins have been established previously. Earlier predictions varied widely on the number of β-strands in its barrel and the orientation of the voltage sensing N terminal remained unresolved. The resolution of the murine VDAC1 at 2.3 Å crystallized in lipidic bicelles gave mechanistic insights into gating and metabolite conductance.
Significance
VDAC sits at the intersection of metabolism and apoptosis and its dysfunction contributes to diseases including cardiovascular disorders and cancer. High resolution structure enables to understand how VDAC regulates mitochondrial permeability and how metabolites and proteins modulate its activity. Precise structural knowledge enables rational drug design aimed at targeting VDAC mediated cell death pathways. Because VDAC interacts with other proteins such has hexokinase and Bcl-2 family members insights into its gating mechanism hold implications for therapeutic control of mitochondrial integrity and metabolic signaling.
Structural highlights
mVDAC1 forms a 19 stranded β-barrel - the first high resolution eukaryotic β-barrel with an odd number of strands. Strands 1 an 19 are in a parallel orientation to close the barrel while the rest are antiparallel. The pore is wide, elliptical and hydrophilic consistent with the open state. A key finding is the well resolved N-terminal α-helix positioned against the barrel's interior wall, partially narrowing the pore and contributing positive charges that shape anion selectivity. The helix is tethered to the wall by multiple hydrogen bonds and connected through a conserved glycine-rich hinge that may enable gating through helix repositioning.
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