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

Zangerl-Plessl, Eva-Maria; Lee, Sun-Joo; Maksaev, Grigory; Bernsteiner, Harald; Ren, Feifei; Yuan, Peng; Stary-Weinzinger, Anna; Nichols, Colin G.

doi:10.1085/jgp.201912422

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

Journal Article · Tue Nov 19 00:00:00 EST 2019 · Journal of General Physiology

DOI:https://doi.org/10.1085/jgp.201912422· OSTI ID:1574555

^[1]; ^[2]; ^[2]; Bernsteiner, Harald ^[1]; Ren, Feifei ^[2]; Yuan, Peng ^[2]; ^[1]; ^[2]

Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
Department of Cell Biology and Physiology and the Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Austrian Science Fund; National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1574555

Alternate ID(s):: OSTI ID: 1581821

Journal Information:: Journal of General Physiology, Journal Name: Journal of General Physiology; ISSN 0022-1295

Country of Publication:: United States

Language:: English

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