Allosteric mechanism of water-channel gating by Ca2+-calmodulin

Nat Struct Mol Biol. 2013 Sep;20(9):1085-92. doi: 10.1038/nsmb.2630. Epub 2013 Jul 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aquaporins / chemistry*
  • Aquaporins / genetics
  • Aquaporins / metabolism*
  • Binding Sites
  • Calmodulin / chemistry*
  • Calmodulin / metabolism*
  • Cattle
  • Eye Proteins / chemistry*
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Hydrophobic and Hydrophilic Interactions
  • Ion Channel Gating
  • Microscopy, Electron
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Mutagenesis, Site-Directed
  • Protein Conformation
  • Protein Stability
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Sheep

Substances

  • Aquaporins
  • Calmodulin
  • Eye Proteins
  • Multiprotein Complexes
  • Recombinant Proteins
  • aquaporin 0

Associated data

  • PDB/3J41