Hinge-bending motions in the pore domain of a bacterial voltage-gated sodium channel

TY - JOUR

T1 - Hinge-bending motions in the pore domain of a bacterial voltage-gated sodium channel

AU - Barber, Annika F.

AU - Carnevale, Vincenzo

AU - Raju, S. G.

AU - Amaral, Cristiano

AU - Treptow, Werner

AU - Klein, Michael L.

N1 - Funding Information: We are grateful for support from the National Institutes of Health , and the Commonwealth of Pennsylvania . We also thank Manuel Covarrubias for very useful scientific discussion. A.F.B. acknowledges the National Institutes of Health (grants NIH-NIAAA T32 AA007463 and NIH-NINDS F31 NS077689 ) for financial support. The National Science Foundation supported this work through XSEDE resources provided by the National Institute for Computational Sciences (grant TG-MCA93S020 ).

PY - 2012/9

Y1 - 2012/9

N2 - Computational methods and experimental data are used to provide structural models for NaChBac, the homo-tetrameric voltage-gated sodium channel from the bacterium Bacillus halodurans, with a closed and partially open pore domain. Molecular dynamic (MD) simulations on membrane-bound homo-tetrameric NaChBac structures, each comprising six helical transmembrane segments (labeled S1 through S6), reveal that the shape of the lumen, which is defined by the bundle of four alpha-helical S6 segments, is modulated by hinge bending motions around the S6 glycine residues. Mutation of these glycine residues into proline and alanine affects, respectively, the structure and conformational flexibility of the S6 bundle. In the closed channel conformation, a cluster of stacked phenylalanine residues from the four S6 helices hinders diffusion of water molecules and Na+ ions. Activation of the voltage sensor domains causes destabilization of the aforementioned cluster of phenylalanines, leading to a more open structure. The conformational change involving the phenylalanine cluster promotes a kink in S6, suggesting that channel gating likely results from the combined action of hinge-bending motions of the S6 bundle and concerted reorientation of the aromatic phenylalanine side-chains.

AB - Computational methods and experimental data are used to provide structural models for NaChBac, the homo-tetrameric voltage-gated sodium channel from the bacterium Bacillus halodurans, with a closed and partially open pore domain. Molecular dynamic (MD) simulations on membrane-bound homo-tetrameric NaChBac structures, each comprising six helical transmembrane segments (labeled S1 through S6), reveal that the shape of the lumen, which is defined by the bundle of four alpha-helical S6 segments, is modulated by hinge bending motions around the S6 glycine residues. Mutation of these glycine residues into proline and alanine affects, respectively, the structure and conformational flexibility of the S6 bundle. In the closed channel conformation, a cluster of stacked phenylalanine residues from the four S6 helices hinders diffusion of water molecules and Na+ ions. Activation of the voltage sensor domains causes destabilization of the aforementioned cluster of phenylalanines, leading to a more open structure. The conformational change involving the phenylalanine cluster promotes a kink in S6, suggesting that channel gating likely results from the combined action of hinge-bending motions of the S6 bundle and concerted reorientation of the aromatic phenylalanine side-chains.

KW - Bacterial channel

KW - Gating

KW - NaChBac

KW - Sodium channel

KW - Voltage gated

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U2 - 10.1016/j.bbamem.2012.05.002

DO - 10.1016/j.bbamem.2012.05.002

M3 - Article

C2 - 22579978

SN - 0005-2736

VL - 1818

SP - 2120

EP - 2125

JO - Biochimica et Biophysica Acta - Biomembranes

JF - Biochimica et Biophysica Acta - Biomembranes

IS - 9

ER -