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Title: Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels

Abstract

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K + ion conduction in the classic inward rectifier Kir2.2, we introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This “forced open” mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP 2 ), an otherwise essential ligand for Kir channel opening. Crystal structures were obtained at a resolution of 3.6 Å without PIP 2 bound, or 2.8 Å in complex with PIP 2 . The latter revealed a slight widening at the helix bundle crossing (HBC) through backbone movement. MD simulations showed that subsequent spontaneous wetting of the pore through the HBC gate region allowed K + ion movement across the HBC and conduction through the channel. Further simulations reveal atomistic details of the opening process and highlight the role of pore-lining acidic residues in K + conduction through Kir2 channels.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [2];  [1];  [2];  [2]; ORCiD logo [1]; ORCiD logo [2]
  1. Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
  2. Department of Cell Biology and Physiology and the Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1574555
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Journal of General Physiology
Additional Journal Information:
Journal Name: Journal of General Physiology; Journal ID: ISSN 0022-1295
Publisher:
Rockefeller University Press
Country of Publication:
United States
Language:
English

Citation Formats

Zangerl-Plessl, Eva-Maria, Lee, Sun-Joo, Maksaev, Grigory, Bernsteiner, Harald, Ren, Feifei, Yuan, Peng, Stary-Weinzinger, Anna, and Nichols, Colin G. Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels. United States: N. p., 2019. Web. doi:10.1085/jgp.201912422.
Zangerl-Plessl, Eva-Maria, Lee, Sun-Joo, Maksaev, Grigory, Bernsteiner, Harald, Ren, Feifei, Yuan, Peng, Stary-Weinzinger, Anna, & Nichols, Colin G. Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels. United States. doi:10.1085/jgp.201912422.
Zangerl-Plessl, Eva-Maria, Lee, Sun-Joo, Maksaev, Grigory, Bernsteiner, Harald, Ren, Feifei, Yuan, Peng, Stary-Weinzinger, Anna, and Nichols, Colin G. Tue . "Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels". United States. doi:10.1085/jgp.201912422.
@article{osti_1574555,
title = {Atomistic basis of opening and conduction in mammalian inward rectifier potassium (Kir2.2) channels},
author = {Zangerl-Plessl, Eva-Maria and Lee, Sun-Joo and Maksaev, Grigory and Bernsteiner, Harald and Ren, Feifei and Yuan, Peng and Stary-Weinzinger, Anna and Nichols, Colin G.},
abstractNote = {Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K + ion conduction in the classic inward rectifier Kir2.2, we introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This “forced open” mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP 2 ), an otherwise essential ligand for Kir channel opening. Crystal structures were obtained at a resolution of 3.6 Å without PIP 2 bound, or 2.8 Å in complex with PIP 2 . The latter revealed a slight widening at the helix bundle crossing (HBC) through backbone movement. MD simulations showed that subsequent spontaneous wetting of the pore through the HBC gate region allowed K + ion movement across the HBC and conduction through the channel. Further simulations reveal atomistic details of the opening process and highlight the role of pore-lining acidic residues in K + conduction through Kir2 channels.},
doi = {10.1085/jgp.201912422},
journal = {Journal of General Physiology},
number = ,
volume = ,
place = {United States},
year = {2019},
month = {11}
}

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