Sponsor
Research in the Hall laboratory is supported by US National Institutes of Health (NIH)/National Eye Institute (NEI) Grant EY5661 (DMC, KLN and JEH). Research by DMC was supported by the (NIH)/National Library of Medicine (NLM) Biomedical Informatics Research Training Program Award #LM007443. Research by SLR was supported by the Ruth L. Kirschtein National Research Service Award from NIH. Research in the Tobias group is supported by (NIH)/National Institute of Neurological Disorders–National Institute of General Medical Sciences (NINDS-NIGMS) Grant GM86685 and US National Science Foundation (NSF) grant CHE-0750175 (AF, MH, and DJT). MH is supported by a fellowship from the German Academy of Sciences Leopoldina. This work was supported in part by NIH grant R01 GM079233 (TG). Research in the Gonen laboratory is funded by the Howard Hughes Medical Institute (SLR and TG).
Published In
Nature Structural and Molecular Biology
Document Type
Post-Print
Publication Date
9-2013
Subjects
Aquaporins, Calmodulin, Electron microscopy, Molecular dynamics, Calcium -- Regulation, Membrane proteins
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, our understanding of the structural mechanisms driving CaM regulation of full-length membrane proteins has remained elusive. In this study, we determined the pseudo-atomic structure of full-length mammalian aquaporin-0 (AQP0, Bos Taurus) in complex with CaM using electron microscopy to understand 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.
DOI
10.1038/nsmb.2630
Persistent Identifier
http://archives.pdx.edu/ds/psu/21413
Citation Details
Reichow, S. L., Clemens, D. M., Freites, J. A., Németh-Cahalan, K. L., Heyden, M., Tobias, D. J., ... & Gonen, T. (2013). Allosteric mechanism of water-channel gating by Ca2+–calmodulin. Nature structural & molecular biology, 20(9), 1085-1092.
Description
This is the authors' version of a manuscript that was subsequently published in Nature Structural and Molecular Biology, 2013 September ; 20(9): 1085–1092. doi:10.1038/nsmb.2630.
Note: At the time of writing, Steve Reichow was affiliated with the Howard Hughes Medical Institute, Ashburn VA.