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Title: Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids

Abstract

Inward rectifier potassium (Kir) channel activity is controlled by plasma membrane lipids. Phosphatidylinositol-4,5-bisphosphate (PIP 2) binding to a primary site is required for opening of classic inward rectifier Kir2.1 and Kir2.2 channels, but interaction of bulk anionic phospholipid (PL -) with a distinct second site is required for high PIP 2sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP 2sensitivity, even in the absence of PL -. Furthermore, high-resolution x-ray crystal structures of Kir2.2[K62W], with or without added PIP 2(2.8- and 2.0-Å resolution, respectively), reveal tight tethering of the C-terminal domain (CTD) to the transmembrane domain (TMD) in each condition. Our results suggest a refined model for phospholipid gating in which PL -binding at the second site pulls the CTD toward the membrane, inducing the formation of the high-affinity primary PIP 2site and explaining the positive allostery between PL -binding and PIP 2sensitivity.

Authors:
; ; ; ; ORCiD logo; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); AHA
OSTI Identifier:
1351381
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of General Physiology; Journal Volume: 148; Journal Issue: 3
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Lee, Sun-Joo, Ren, Feifei, Zangerl-Plessl, Eva-Maria, Heyman, Sarah, Stary-Weinzinger, Anna, Yuan, Peng, and Nichols, Colin G. Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids. United States: N. p., 2016. Web. doi:10.1085/jgp.201611616.
Lee, Sun-Joo, Ren, Feifei, Zangerl-Plessl, Eva-Maria, Heyman, Sarah, Stary-Weinzinger, Anna, Yuan, Peng, & Nichols, Colin G. Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids. United States. doi:10.1085/jgp.201611616.
Lee, Sun-Joo, Ren, Feifei, Zangerl-Plessl, Eva-Maria, Heyman, Sarah, Stary-Weinzinger, Anna, Yuan, Peng, and Nichols, Colin G. 2016. "Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids". United States. doi:10.1085/jgp.201611616.
@article{osti_1351381,
title = {Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids},
author = {Lee, Sun-Joo and Ren, Feifei and Zangerl-Plessl, Eva-Maria and Heyman, Sarah and Stary-Weinzinger, Anna and Yuan, Peng and Nichols, Colin G.},
abstractNote = {Inward rectifier potassium (Kir) channel activity is controlled by plasma membrane lipids. Phosphatidylinositol-4,5-bisphosphate (PIP2) binding to a primary site is required for opening of classic inward rectifier Kir2.1 and Kir2.2 channels, but interaction of bulk anionic phospholipid (PL-) with a distinct second site is required for high PIP2sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP2sensitivity, even in the absence of PL-. Furthermore, high-resolution x-ray crystal structures of Kir2.2[K62W], with or without added PIP2(2.8- and 2.0-Å resolution, respectively), reveal tight tethering of the C-terminal domain (CTD) to the transmembrane domain (TMD) in each condition. Our results suggest a refined model for phospholipid gating in which PL-binding at the second site pulls the CTD toward the membrane, inducing the formation of the high-affinity primary PIP2site and explaining the positive allostery between PL-binding and PIP2sensitivity.},
doi = {10.1085/jgp.201611616},
journal = {Journal of General Physiology},
number = 3,
volume = 148,
place = {United States},
year = 2016,
month = 8
}
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