Biochemistry

Four Closure

See allHide authors and affiliations

Science  06 Sep 2013:
Vol. 341, Issue 6150, pp. 1045
DOI: 10.1126/science.341.6150.1045-a
CREDIT: S. L. REICHOW ET AL., NATURE STRUCTURE & MOLECULAR BIOLOGY 20 (28 JULY 2013) © 2013 NATURE PUBLISHING GROUP

The Ca2+-binding protein calmodulin (CaM) is involved in the regulation of many membrane channels, but how it modulates permeability remains unclear. Reichow et al. have combined electron microscopy, structural modeling, molecular dynamics, and mutagenesis to study the interaction of the aquaporin AQP0 and CaM. Each monomer in the tetrameric AQP0 contains a water-conducting pore. Fitting crystal structures of the AQP0 tetramer and CaM into a 25 Å electron microscopic reconstruction revealed that CaM bound to the C-terminal helices of adjacent AQP0 monomers. Initially, CaM binds to one helix, and its proximity to the neighboring monomer then allows it to capture the second one. Molecular dynamics simulations suggested that, although it only links two monomers, CaM restricts the dynamics of all four monomers in the tetramer. The constriction site CSII at the cytoplasmic vestibule of the channel has been proposed to gate access. Interestingly, the AQP0 residues that were stabilized most by CaM mapped to the C-terminal helices, the base of the last transmembrane helix, and residues that form CSII. In AQP0, tetramerization is not required for water permeability; however, these results show that its quaternary structure facilitates cooperative regulation, and the regulation of other membrane channels by CaM may rely on similar mechanisms.

Nat. Struct. Mol. Biol. 20, 10.1038/nsmb.2630 (2013).

Navigate This Article