Document Detail

The anion-selective pore of the bestrophins, a family of chloride channels associated with retinal degeneration.
MedLine Citation:
PMID:  16707793     Owner:  NLM     Status:  MEDLINE    
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.
Zhiqiang Qu; Li-Ting Chien; Yuanyuan Cui; H Criss Hartzell
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
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:
Created Date:  2006-05-18     Completed Date:  2006-06-08     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5411-9     Citation Subset:  IM    
Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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MeSH Terms
Amino Acid Sequence / 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
Patch-Clamp Techniques
Protein Structure, Tertiary / genetics
Retina / cytology,  metabolism*,  physiopathology
Retinal Degeneration / genetics,  metabolism*,  physiopathology
Grant Support
Reg. No./Substance:
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

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