Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications
Abstract
The voltage-dependent, anion-selective channel (VDAC) is generally considered the main pathway for metabolite diffusion across the mitochondrial outer membrane. It also interacts with several mitochondrial and cytosolic proteins, including kinases and cytochrome c. Sequence analysis and circular dichroism suggest that the channel is a bacterial porin-like beta-barrel. However, unlike bacterial porins, VDAC does not form tight trimeric complexes and is easily gated (reversibly closed) by membrane potential and low pH. Circular dichroism indicates that the protein undergoes a major conformational change at pH < 5, involving decreased beta-sheet and increased alpha-helical content. Electron microscopy of two-dimensional crystals of fungal VDAC provides direct information about the size and shape of its lumen and suggests that the N-terminal domain forms a mobile alpha-helix. It is proposed that the N-terminal domain normally resides in a groove in the lumen wall and that gating stimuli favor its displacement, destabilizing the putative beta-barrel. Partial closure would result from subsequent larger-scale structural rearrangements in the protein, possibly corresponding to the conformational change observed at pH < 5.
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