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Nature Structural and Molecular Biology

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Aquaporins, Calmodulin, Electron microscopy, Molecular dynamics, Calcium -- Regulation, Membrane proteins


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.


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.



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