?-Barrel mobility underlies closure of the voltage-dependent anion channel.

ABSTRACT: The voltage-dependent anion channel (VDAC) is the major protein in the outer mitochondrial membrane, where it mediates transport of ATP and ADP. Changes in its permeability, induced by voltage or apoptosis-related proteins, have been implicated in apoptotic pathways. The three-dimensional structure of VDAC has recently been determined as a 19-stranded ?-barrel with an in-lying N-terminal helix. However, its gating mechanism is still unclear. Using solid-state NMR spectroscopy, molecular dynamics simulations, and electrophysiology, we show that deletion of the rigid N-terminal helix sharply increases overall motion in VDAC's ?-barrel, resulting in elliptic, semicollapsed barrel shapes. These states quantitatively reproduce conductance and selectivity of the closed VDAC conformation. Mutation of the N-terminal helix leads to a phenotype intermediate to the open and closed states. These data suggest that the N-terminal helix controls entry into elliptic ?-barrel states which underlie VDAC closure. Our results also indicate that ?-barrel channels are intrinsically flexible.

SUBMITTER: Zachariae U 

PROVIDER: S-EPMC5650048 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature