The ion 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 b-barrel. However, unlike bacterial porins, VDAC does not form symmetrical 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 less than 5, involving decreased b-sheet and increased a-helical content.















Electron microscopy of two-dimensional crystals of fungal VDAC is providing direct information about the size and shape of its lumen. The figure shows a 3D model of VDAC obtained by electron crystallography at a resolution of about 17 Å. The inner diameter of the pore is about 25 Å and there is a large diagonal groove in the lumen that is clearly visible in the above views. The N-terminal domain forms a mobile a-helix that extends from the pore in some crystal polymorphs (not shown in the above model). It has been proposed that the N-terminal domain may normally reside in the groove in the lumen wall and that gating stimuli favor its displacement, destabilizing the putative b-barrel. Partial closure would result from subsequent larger-scale structural rearrangements in the protein, possibly corresponding to the conformational change observed at pH less than 5.

References
Mannella (1998), J. Struct. Biol. 121:207-218
Mannella (1997), J. Bioenerg. Biomembr. 29:525-531

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