title: Structure and insights into the function of a Ca(2+)-activated Cl(-) channel.
abstract: Bestrophin calcium-activated chloride channels (CaCCs) regulate the flow of chloride and other monovalent anions across cellular membranes in response to intracellular calcium (Ca(2+)) levels. Mutations in bestrophin 1 (BEST1) cause certain eye diseases. Here we present X-ray structures of chicken BEST1-Fab complexes, at 2.85 Å resolution, with permeant anions and Ca(2+). Representing, to our knowledge, the first structure of a CaCC, the eukaryotic BEST1 channel, which recapitulates CaCC function in liposomes, is formed from a pentameric assembly of subunits. Ca(2+) binds to the channel's large cytosolic region. A single ion pore, approximately 95 Å in length, is located along the central axis and contains at least 15 binding sites for anions. A hydrophobic neck within the pore probably forms the gate. Phenylalanine residues within it may coordinate permeating anions via anion-π interactions. Conformational changes observed near the 'Ca(2+) clasp' hint at the mechanism of Ca(2+)-dependent gating. Disease-causing mutations are prevalent within the gating apparatus.
authors.affiliation: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Kane Dickson
authors.affiliation: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Leanne
authors.initials: L
authors.lastname: Pedi
authors.affiliation: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Long
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002645:Chickens; D018118:Chloride Channels / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D002712:Chlorides / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D015640:Ion Channel Gating; D017136:Ion Transport; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D002118:Calcium