Functional dynamics in the voltage-dependent anion channel

TY - JOUR

T1 - Functional dynamics in the voltage-dependent anion channel

AU - Villinger, S.

AU - Briones, R.

AU - Giller, K.

AU - Zachariae, Ulrich

AU - Lange, A.

AU - De Groot, B.L.

AU - Griesinger, C.

AU - Becker, S.

AU - Zweckstetter, M.

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

PY - 2010/12/28

Y1 - 2010/12/28

N2 - The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites. Here we reveal functional dynamics of isoform one of VDAC (VDAC1) by a combination of solution NMR spectroscopy, Gaussian network model analysis, and molecular dynamics simulation. Micro- to millisecond dynamics are significantly increased for the N-terminal six ß-strands of VDAC1 in micellar solution, in agreement with increased B-factors observed in the same region in the bicellar crystal structure of VDAC1. Molecular dynamics simulations reveal that a charge on the membrane-facing glutamic acid 73 (E73) accounts for the elevation of N-terminal protein dynamics as well as a thinning of the nearby membrane. Mutation or chemical modification of E73 strongly reduces the micro- to millisecond dynamics in solution. Because E73 is necessary for hexokinase-I-induced VDAC channel closure and inhibition of apoptosis, our results imply that microto millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.

AB - The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites. Here we reveal functional dynamics of isoform one of VDAC (VDAC1) by a combination of solution NMR spectroscopy, Gaussian network model analysis, and molecular dynamics simulation. Micro- to millisecond dynamics are significantly increased for the N-terminal six ß-strands of VDAC1 in micellar solution, in agreement with increased B-factors observed in the same region in the bicellar crystal structure of VDAC1. Molecular dynamics simulations reveal that a charge on the membrane-facing glutamic acid 73 (E73) accounts for the elevation of N-terminal protein dynamics as well as a thinning of the nearby membrane. Mutation or chemical modification of E73 strongly reduces the micro- to millisecond dynamics in solution. Because E73 is necessary for hexokinase-I-induced VDAC channel closure and inhibition of apoptosis, our results imply that microto millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.

UR - https://www.scopus.com/pages/publications/78651092981

U2 - 10.1073/pnas.1012310108

DO - 10.1073/pnas.1012310108

M3 - Article

C2 - 21148773

AN - SCOPUS:78651092981

SN - 0027-8424

VL - 107

SP - 22546

EP - 22551

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 52

ER -