The N-terminus of VDAC: Structure, mutational analysis, and a potential role in regulating barrel shape

• Several models of voltage-sensitive gating of VDAC invoke movement of its helix-rich N-terminus.
• Multiple interactions occur between the central part of the N-terminus and the barrel.
• The N-terminus may reversibly stabilize the barrel in an open state.
• The N-terminus weakly interacts with ATP during its transport.
• The role of the N-terminus in VDAC dimerization is yet to be resolved.

A novel feature of the voltage-dependent anion channel (VDAC, mitochondrial porin), is the barrel, comprising an odd number of β-strands and closed by parallel strands. Recent research has focused on the N-terminal segment, which in the available structures, resides in the lumen and is not part of the barrel. In this review, the structural data obtained from vertebrate VDAC are integrated with those from VDAC in artificial bilayers, emphasizing the array of native and tagged versions of VDAC used. The data are discussed with respect to a recent gating model (Zachariae et al. (2012) Structure 20:1–10), in which the N-terminus acts not as a gate on a stable barrel, but rather stabilizes the barrel, preventing its shift into a partially collapsed, low-conductance, closed state. Additionally, the role of the N-terminus in VDAC oligomerization, apoptosis through interactions with hexokinase and its interaction with ATP are discussed briefly.

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