@article{8c76cfe7f8dd48d6a6ece861ff939eb1,
title = "Allosteric mechanism of water-channel gating by Ca 2+ -calmodulin",
abstract = "Calmodulin (CaM) is a universal regulatory protein that communicates the presence of calcium to its molecular targets and correspondingly modulates their function. This key signaling protein is important for controlling the activity of hundreds of membrane channels and transporters. However, understanding of the structural mechanisms driving CaM regulation of full-length membrane proteins has remained elusive. In this study, we determined the pseudoatomic structure of full-length mammalian aquaporin-0 (AQP0, Bos taurus) in complex with CaM, using EM to elucidate how this signaling protein modulates water-channel function. Molecular dynamics and functional mutation studies reveal how CaM binding inhibits AQP0 water permeability by allosterically closing the cytoplasmic gate of AQP0. Our mechanistic model provides new insight, only possible in the context of the fully assembled channel, into how CaM regulates multimeric channels by facilitating cooperativity between adjacent subunits.",
author = "Reichow, {Steve L.} and Clemens, {Daniel M.} and Freites, {J. Alfredo} and N{\'e}meth-Cahalan, {Karin L.} and Matthias Heyden and Tobias, {Douglas J.} and Hall, {James E.} and Tamir Gonen",
note = "Funding Information: The authors would like to thank M. Sarhan (Howard Hughes Medical Institute (HHMI), Janelia Farm Research Campus) for help with ITC and D. Shi (HHMI, Janelia Farm Research Campus) for help with various aspects of EM. Research in the laboratory of J.E.H. is supported by US National Institutes of Health (NIH) National Eye Institute grant EY5661 (J.E.H.). Research by D.M.C. was supported by the NIH National Library of Medicine Biomedical Informatics Research Training Program Award, no. LM007443. Research by S.L.R. was supported by the Ruth L. Kirschtein National Research Service Award from NIH. Research in the laboratory of D.J.T. is supported by NIH National Institute of Neurological Disorders– National Institute of General Medical Sciences grant GM86685 and US National Science Foundation grant CHE-0750175 (D.J.T.). M.H. is supported by a fellowship from the German Academy of Sciences Leopoldina. This work was supported in part by NIH grant R01 GM079233 (T.G.). Research in the laboratory of T.G. is funded by the HHMI (T.G.).",
year = "2013",
month = sep,
doi = "10.1038/nsmb.2630",
language = "English (US)",
volume = "20",
pages = "1085--1092",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "9",
}