The pore domain outer helix contributes to both activation and inactivation of the HERG K⁺ channel

Ju, Pengchu, Pages, Guilhem, Riek, R. Peter, Chen, Po-chia, Torres, Allan M., Bansal, Paramjit, Kuyucak, Serdar, Kuchel, Philip W., and Vandenberg, Jamie I. (2009) The pore domain outer helix contributes to both activation and inactivation of the HERG K⁺ channel. Journal of Biological Chemistry, 284 (2). pp. 1000-1008.

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Ion flow in many voltage-gated K⁺ channels (VGK), including the (human ether-a-go-go-related gene) hERG channel, is regulated by reversible collapse of the selectivity filter. hERG channels, however, exhibit low sequence homology to other VGKs, particularly in the outer pore helix (S5) domain, and we hypothesize that this contributes to the unique activation and inactivation kinetics in hERG K⁺ channels that are so important for cardiac electrical activity. The S5 domain in hERG identified by NMR spectroscopy closely corresponded to the segment predicted by bioinformatics analysis of 676 members of the VGK superfamily. Mutations to approximately every third residue, from Phe^551 to Trp^563, affected steady state activation, whereas mutations to approximately every third residue on an adjacent face and spanning the entire S5 segment perturbed inactivation, suggesting that the whole span of S5 experiences a rearrangement associated with inactivation. We refined a homology model of the hERG pore domain using constraints from the mutagenesis data with residues affecting inactivation pointing in toward S6. In this model the three residues with maximum impact on activation (W563A, F559A, and F551A) face out toward the voltage sensor. In addition, the residues that when mutated to alanine, or from alanine to valine, that did not express (Ala^561, His^562, Ala^565, Trp^568, and Ile^571), all point toward the pore helix and contribute to close hydrophobic packing in this region of the channel.

Item ID: 32518
Item Type: Article (Research - C1)
ISSN: 1083-351X
Date Deposited: 25 Aug 2014 05:53
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110101 Medical Biochemistry: Amino Acids and Metabolites @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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