title: Allosteric mechanism of water-channel gating by Ca2+-calmodulin.
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.
authors.affiliation: 1] Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA. [2].
authors.forename: Steve L
authors.initials: SL
authors.lastname: Reichow
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Clemens
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Freites
authors.forename: Karin L
authors.initials: KL
authors.lastname: Németh-Cahalan
authors.forename: Matthias
authors.initials: M
authors.lastname: Heyden
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Tobias
authors.forename: James E
authors.initials: JE
authors.lastname: Hall
authors.forename: Tamir
authors.initials: T
authors.lastname: Gonen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020346:Aquaporins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism*; D002417:Cattle; D005136:Eye Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating; D008854:Microscopy, Electron; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012756:Sheep
chemical_list: D020346:Aquaporins; D002147:Calmodulin; D005136:Eye Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C030328:aquaporin 0
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