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

Journal Article · · Journal of General Physiology
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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.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); AHA
OSTI ID:
1351381
Journal Information:
Journal of General Physiology, Vol. 148, Issue 3; ISSN 0022-1295
Country of Publication:
United States
Language:
ENGLISH

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