Molecular Plasticity of the Human Voltage-Dependent Anion Channel Embedded Into a Membrane

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 Ca2+, 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. [Display omitted] •Human VDAC1 in the membrane is structurally flexible•The β barrel of human VDAC can stepwise unfold β hairpins•Ca2+ considerably decreases the conformational variability of hVDAC1•Ca2+ considerably decreases the free energy stabilizing hVDAC1 VDAC is the primary gatekeeper of mitochondria. Ge et al. use single-molecule force spectroscopy in combination with NMR spectroscopy to show that the membrane-embedded barrel of human VDAC is highly flexible. Because calcium considerably decreases the pore's conformational variability, this modulation might provide the means to influence VDAC function.