CFTR氯离子通道―跨上皮离子转运的多功能引擎.pdfVIP

416 Acta Physiologica Sinica , August 25, 2007, 59 (4): 416-430 Review - The cystic fibrosis transmembrane conductance regulator Cl channel: a versatile engine for transepithelial ion transport 1 1 2 1 1 1,* Hongyu LI , Zhiwei CAI , Jeng-Haur CHEN , Min JU , Zhe XU , David N. SHEPPARD 1Department of Physiology, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK; 2Howard Hughes Medical Institute and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporter superfamily that forms a Cl- channel with complex regulation. CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs) and a unique regulatory domain (RD). The MSDs assemble to form a low conductance (6-10 pS) anion-selective pore with deep intracellular and shallow extracellular vestibules separated by a selectivity filter. The NBDs form a head-to-tail dimer with two ATP-binding sites (termed sites 1 and 2) located at the dimer interface. Anion flow through CFTR is gated by the interaction of ATP with sites 1 and 2 powering cycles of NBD dimer association and dissociation and hence, conformational changes in the MSDs that open and close the channel pore. The RD is an unstructured domain with multiple consensus phosphorylation sites, phosphorylation of which stimulates CFTR function by enhancing the interaction of ATP wit