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Int. J. Mol. Sci. 2015, 16(1), 1627-1643; doi:10.3390/ijms16011627

Caution Is Required in Interpretation of Mutations in the Voltage Sensing Domain of Voltage Gated Channels as Evidence for Gating Mechanisms

Department of Chemistry, City College of New York, 160 Convent Avenue, New York, NY 10031, USA
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Author to whom correspondence should be addressed.
Academic Editor: Bing Yan
Received: 19 December 2014 / Accepted: 8 January 2015 / Published: 12 January 2015
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

The gating mechanism of voltage sensitive ion channels is generally considered to be the motion of the S4 transmembrane segment of the voltage sensing domains (VSD). The primary supporting evidence came from R→C mutations on the S4 transmembrane segment of the VSD, followed by reaction with a methanethiosulfonate (MTS) reagent. The cys side chain is –SH (reactive form –S); the arginine side chain is much larger, leaving space big enough to accommodate the MTS sulfonate head group. The cavity created by the mutation has space for up to seven more water molecules than were present in wild type, which could be displaced irreversibly by the MTS reagent. Our quantum calculations show there is major reorientation of three aromatic residues that face into the cavity in response to proton displacement within the VSD. Two phenylalanines reorient sufficiently to shield/unshield the cysteine from the intracellular and extracellular ends, depending on the proton positions, and a tyrosine forms a hydrogen bond to the cysteine sulfur with its side chain –OH. These could produce the results of the experiments that have been interpreted as evidence for physical motion of the S4 segment, without physical motion of the S4 backbone. The computations strongly suggest that the interpretation of cysteine substitution reaction experiments be re-examined in the light of these considerations. View Full-Text
Keywords: voltage gating; quantum calculations; substituted cysteine accessibility method; proton transport; voltage sensing domain voltage gating; quantum calculations; substituted cysteine accessibility method; proton transport; voltage sensing domain
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kariev, A.M.; Green, M.E. Caution Is Required in Interpretation of Mutations in the Voltage Sensing Domain of Voltage Gated Channels as Evidence for Gating Mechanisms. Int. J. Mol. Sci. 2015, 16, 1627-1643.

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