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Sun-Joo Lee
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Journal Articles
Eva-Maria Zangerl-Plessl, Sun-Joo Lee, Grigory Maksaev, Harald Bernsteiner, Feifei Ren, Peng Yuan, Anna Stary-Weinzinger, Colin G. Nichols
Journal:
Journal of General Physiology
Journal of General Physiology (2019) 152 (1): e201912422.
Published: 19 November 2019
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.
Includes: Supplementary data
Journal Articles
Sun-Joo Lee, Feifei Ren, Eva-Maria Zangerl-Plessl, Sarah Heyman, Anna Stary-Weinzinger, Peng Yuan, Colin G. Nichols
Journal:
Journal of General Physiology
Journal of General Physiology (2016) 148 (3): 227–237.
Published: 15 August 2016
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 2 sensitivity. Here we show that introduction of a lipid-partitioning tryptophan at the second site (K62W) generates high PIP 2 sensitivity, 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 2 site and explaining the positive allostery between PL − binding and PIP 2 sensitivity.
Includes: Supplementary data
Journal Articles
Journal:
Journal of General Physiology
Journal of General Physiology (2015) 146 (6): 527–540.
Published: 30 November 2015
Abstract
Cantú syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9 , which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (K ATP ) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium ( 86 Rb + ) efflux assays, we show that K ATP channels formed with P429L, A475V, or C1039Y mutants enhance K ATP activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive K ATP channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.