A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P(2).

@article{citeulike:3281322, abstract = {Inwardly rectifying potassium (Kir) channels are gated by the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)). Among them, Kir3 requires additional molecules, such as the betagamma subunits of G proteins or intracellular sodium, for channel gating. Using an interactive computational-experimental approach, we show that sodium sensitivity of Kir channels involves the side chains of an aspartate and a histidine located across from each other in a crucial loop in the cytosolic domain, as well as the backbone carbonyls of two more residues and a water molecule. The location of the coordination site in the vicinity of a conserved arginine shown to affect channel-PtdIns(4,5)P(2) interactions suggests that sodium triggers a structural switch that frees the crucial arginine. Mutations of the aspartate and the histidine that affect sodium sensitivity also enhance the channel's sensitivity to PtdIns(4,5)P(2). Furthermore, on the basis of the molecular characteristics of the coordination site, we identify and confirm experimentally a sodium-sensitive phenotype in Kir5.1.}, address = {[1] Department of Structural and Chemical Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA. [2] Present addresses: Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago, 840 South Wood Street (M/C 719), Room 920-N CSB, Chicago, Illinois 60612, USA (A.R.-D.), CombinatoRx Inc., 245 First Street, Cambridge, Massachusetts 02142, USA (J.L.S.), Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA (R.R.) and Virginia Commonwealth University, Medical College of Virginia Campus, Department of Physiology and Biophysics, Sanger Hall 3-005, 1101 East Marshall Street, Richmond, Virginia 23298, USA (D.E.L.).}, author = {Rosenhouse-Dantsker, Avia and Sui, Jin L L. and Zhao, Qi and Rusinova, Radda and Rodr\'{i}guez-Menchaca, Aldo A A. and Zhang, Zhe and Logothetis, Diomedes E E. }, citeulike-article-id = {3281322}, doi = {http://dx.doi.org/10.1038/nchembio.112}, issn = {1552-4469}, journal = {Nature chemical biology}, keywords = {kir, md, pip2, sodium}, month = {September}, posted-at = {2008-09-17 17:49:36}, priority = {2}, title = {A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P(2).}, url = {http://dx.doi.org/10.1038/nchembio.112}, year = {2008} }

TY - JOUR ID - citeulike:3281322 L3 - citeulike-article-id:3281322 N2 - Inwardly rectifying potassium (Kir) channels are gated by the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)). Among them, Kir3 requires additional molecules, such as the betagamma subunits of G proteins or intracellular sodium, for channel gating. Using an interactive computational-experimental approach, we show that sodium sensitivity of Kir channels involves the side chains of an aspartate and a histidine located across from each other in a crucial loop in the cytosolic domain, as well as the backbone carbonyls of two more residues and a water molecule. The location of the coordination site in the vicinity of a conserved arginine shown to affect channel-PtdIns(4,5)P(2) interactions suggests that sodium triggers a structural switch that frees the crucial arginine. Mutations of the aspartate and the histidine that affect sodium sensitivity also enhance the channel's sensitivity to PtdIns(4,5)P(2). Furthermore, on the basis of the molecular characteristics of the coordination site, we identify and confirm experimentally a sodium-sensitive phenotype in Kir5.1. JF - Nature chemical biology SN - 1552-4469 AD - [1] Department of Structural and Chemical Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA. [2] Present addresses: Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago, 840 South Wood Street (M/C 719), Room 920-N CSB, Chicago, Illinois 60612, USA (A.R.-D.), CombinatoRx Inc., 245 First Street, Cambridge, Massachusetts 02142, USA (J.L.S.), Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA (R.R.) and Virginia Commonwealth University, Medical College of Virginia Campus, Department of Physiology and Biophysics, Sanger Hall 3-005, 1101 East Marshall Street, Richmond, Virginia 23298, USA (D.E.L.). TI - A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P(2). KW - kir KW - md KW - pip2 KW - sodium AU - Rosenhouse-Dantsker, Avia AU - Sui, Jin L AU - Zhao, Qi AU - Rusinova, Radda AU - Rodríguez-Menchaca, Aldo A AU - Zhang, Zhe AU - Logothetis, Diomedes E PY - 2008/09/14/ UR - http://dx.doi.org/10.1038/nchembio.112 ER -