| The anion-selective pore of the bestrophins, a family of chloride channels associated with retinal degeneration. | |
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MedLine Citation:
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PMID: 16707793 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in human bestrophin-1 (VMD2) are genetically linked to a juvenile form of macular degeneration and autosomal dominant vitreoretinochoroidopathy. Recently, it has been proposed that bestrophins are Cl- channels and that the putative second transmembrane domain participates in forming the bestrophin pore. However, the structural determinants of Cl- ion permeation through the channel pore are not known. Here we systematically replaced every amino acid in mouse bestrophin-2 (mBest2) between positions 69 and 104 with cysteine. We then measured the effects on the relative permeability and conductance of the channel to Cl- and SCN- (thiocyanate) and determined the accessibility of the cysteine-substituted amino acids to extracellularly applied, membrane-impermeant sulfhydryl reagents. Unlike K+ channels, the amino acids forming the mBest2 selectivity filter are not discretely localized but are distributed over approximately 20 amino acids within the transmembrane domain. Cysteine-substituted amino acids in the selectivity filter are easily accessible to extracellularly applied sulfhydryl reagents and select for anionic sulfhydryl reagents over cationic ones. Understanding the structure of the anion conduction pathway of bestrophins provides insights into how mutations produce channel dysfunction and may provide important information for development of therapeutic strategies for treating macular degeneration. |
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Authors:
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Zhiqiang Qu; Li-Ting Chien; Yuanyuan Cui; H Criss Hartzell |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 26 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2006 May |
Date Detail:
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Created Date: 2006-05-18 Completed Date: 2006-06-08 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 5411-9 Citation Subset: IM |
Affiliation:
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Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence
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physiology Amino Acid Substitution / genetics Amino Acids / chemistry, pharmacology Cell Line Chloride Channels / genetics, metabolism* Chlorides / metabolism, pharmacology Cysteine / genetics, metabolism Eye Proteins / chemistry, genetics, metabolism* Green Fluorescent Proteins Humans Patch-Clamp Techniques Protein Structure, Tertiary / genetics Retina / cytology, metabolism*, physiopathology Retinal Degeneration / genetics, metabolism*, physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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EY014852/EY/NEI NIH HHS; GM60448/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids; 0/BEST1 protein, human; 0/Chloride Channels; 0/Chlorides; 0/Eye Proteins; 147336-22-9/Green Fluorescent Proteins; 52-90-4/Cysteine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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