Structure and insights into the function of a Ca2+-activated Cl− channel

Veronica Kane Dickson, Leanne Pedi and Stephen B. Long ()
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Veronica Kane Dickson: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Leanne Pedi: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Stephen B. Long: Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA

Nature, 2014, vol. 516, issue 7530, 213-218

Abstract: Abstract Bestrophin calcium-activated chloride channels (CaCCs) regulate the flow of chloride and other monovalent anions across cellular membranes in response to intracellular calcium (Ca2+) 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 Ca2+. 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. Ca2+ 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 ‘Ca2+ clasp’ hint at the mechanism of Ca2+-dependent gating. Disease-causing mutations are prevalent within the gating apparatus.

Date: 2014
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DOI: 10.1038/nature13913

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