Allosteric mechanism of water-channel gating by Ca 2+ -calmodulin

Steve L. Reichow, Daniel M. Clemens, J. Alfredo Freites, Karin L. Németh-Cahalan, Matthias Heyden, Douglas J. Tobias, James E. Hall, Tamir Gonen

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1085-1092
Number of pages8
JournalNature Structural and Molecular Biology
Volume20
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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