β-Barrel mobility underlies closure of the voltage-dependent anion channel

TY - JOUR

T1 - β-Barrel mobility underlies closure of the voltage-dependent anion channel

AU - Zachariae, Ulrich

AU - Schneider, Robert

AU - Briones, Rodolfo

AU - Gattin, Zrinka

AU - Demers, Jean-Phillipe

AU - Giller, Karin

AU - Maier, Elke

AU - Zweckstetter, Markus

AU - Griesinger, C.

AU - Becker, Stefan

AU - Benz, Roland

AU - De Groot, Bert L.

AU - Lange, Adam

N1 - MEDLINE® is the source for the MeSH terms of this document.

PY - 2012

Y1 - 2012

N2 - 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 ß-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 ß-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 ß-barrel states which underlie VDAC closure. Our results also indicate that ß-barrel channels are intrinsically flexible.

AB - 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 ß-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 ß-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 ß-barrel states which underlie VDAC closure. Our results also indicate that ß-barrel channels are intrinsically flexible.

UR - https://www.scopus.com/pages/publications/84865760948

U2 - 10.1016/j.str.2012.06.015

DO - 10.1016/j.str.2012.06.015

M3 - Article

C2 - 22841291

AN - SCOPUS:84865760948

SN - 0969-2126

VL - 20

SP - 1540

EP - 1549

JO - Structure

JF - Structure

IS - 9

ER -