Publication Date:
2014-10-23
Description:
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 A 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 A 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-pi 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454446/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454446/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kane Dickson, Veronica -- Pedi, Leanne -- Long, Stephen B -- P30 CA008748/CA/NCI NIH HHS/ -- R01 GM110396/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Dec 11;516(7530):213-8. doi: 10.1038/nature13913. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337878" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Binding Sites
;
Calcium/analysis/chemistry/*metabolism/pharmacology
;
*Chickens
;
Chloride Channels/*chemistry/immunology/*metabolism
;
Chlorides/chemistry/metabolism
;
Crystallography, X-Ray
;
Immunoglobulin Fab Fragments/chemistry/immunology
;
Ion Channel Gating
;
Ion Transport
;
Liposomes/chemistry/metabolism
;
Models, Molecular
;
Structure-Activity Relationship
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
