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

International Journal of Molecular Sciences

Alisher M. Kariev²  Michael E. Green¹ 

[1] Department of Chemistry, City College of New York, 160 Convent Avenue, New York, NY 10031, USA; E-Mail

关键词: voltage gating;    quantum calculations;    substituted cysteine accessibility method;    proton transport;    voltage sensing domain;   

DOI  :  10.3390/ijms16011627

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.