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Mechanistic insight into human ether-à-go-go-related gene (hERG) K+ channel deactivation gating from the solution structure of the EAG domain.

Muskett FW, Thouta S, Thomson SJ, Bowen A, Stansfeld PJ, Mitcheson JS
J Biol Chem 286 6184-91 (2011)
Cited: 78 times
EuropePMC logo PMID: 21135103

Abstract

Human ether-à-go-go-related gene (hERG) K(+) channels have a critical role in cardiac repolarization. hERG channels close (deactivate) very slowly, and this is vital for regulating the time course and amplitude of repolarizing current during the cardiac action potential. Accelerated deactivation is one mechanism by which inherited mutations cause long QT syndrome and potentially lethal arrhythmias. hERG deactivation is highly dependent upon an intact EAG domain (the first 135 amino acids of the N terminus). Importantly, deletion of residues 2-26 accelerates deactivation to a similar extent as removing the entire EAG domain. These and other experiments suggest the first 26 residues (NT1-26) contain structural elements required to slow deactivation by stabilizing the open conformation of the pore. Residues 26-135 form a Per-Arnt-Sim domain, but a structure for NT1-26 has not been forthcoming, and little is known about its site of interaction on the channel. In this study, we present an NMR structure for the entire EAG domain, which reveals that NT1-26 is structurally independent from the Per-Arnt-Sim domain and contains a stable amphipathic helix with one face being positively charged. Mutagenesis and electrophysiological studies indicate that neutralizing basic residues and breaking the amphipathic helix dramatically accelerate deactivation. Furthermore, scanning mutagenesis and molecular modeling studies of the cyclic nucleotide binding domain suggest that negatively charged patches on its cytoplasmic surface form an interface with the NT1-26 domain. We propose a model in which NT1-26 obstructs gating motions of the cyclic nucleotide binding domain to allosterically stabilize the open conformation of the pore.

Reviews - 2l1m mentioned but not cited (2)

  1. HERG potassium channel regulation by the N-terminal eag domain. Gustina AS, Trudeau MC. Cell. Signal. 24 1592-1598 (2012)
  2. The EAG Voltage-Dependent K+ Channel Subfamily: Similarities and Differences in Structural Organization and Gating. Barros F, de la Peña P, Domínguez P, Sierra LM, Pardo LA. Front Pharmacol 11 411 (2020)

Articles - 2l1m mentioned but not cited (2)

  1. Mechanistic insight into human ether-à-go-go-related gene (hERG) K+ channel deactivation gating from the solution structure of the EAG domain. Muskett FW, Thouta S, Thomson SJ, Bowen A, Stansfeld PJ, Mitcheson JS. J. Biol. Chem. 286 6184-6191 (2011)
  2. The structural mechanism of KCNH-channel regulation by the eag domain. Haitin Y, Carlson AE, Zagotta WN. Nature 501 444-448 (2013)


Reviews citing this publication (14)

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  4. Towards a Structural View of Drug Binding to hERG K+ Channels. Vandenberg JI, Perozo E, Allen TW. Trends Pharmacol. Sci. 38 899-907 (2017)
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  11. Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients. Ono M, Burgess DE, Schroder EA, Elayi CS, Anderson CL, January CT, Sun B, Immadisetty K, Kekenes-Huskey PM, Delisle BP. Biomolecules 10 (2020)
  12. Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics. Zequn Z, Jiangfang L. Front Pharmacol 12 687007 (2021)
  13. New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question. Barros F, Pardo LA, Domínguez P, Sierra LM, de la Peña P. Int J Mol Sci 20 (2019)
  14. Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome. Brewer KR, Kuenze G, Vanoye CG, George AL, Meiler J, Sanders CR. Front Pharmacol 11 550 (2020)

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