{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T08:56:11Z","timestamp":1762505771908},"reference-count":64,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,6,1]]},"abstract":"<jats:p>Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel belonging to the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily. ABC proteins share a common molecular mechanism that couples ATP binding and hydrolysis at two nucleotide-binding domains (NBDs) to diverse functions. This involves formation of NBD dimers, with ATP bound at two composite interfacial sites. In CFTR, intramolecular NBD dimerization is coupled to channel opening. Channel closing is triggered by hydrolysis of the ATP molecule bound at composite site 2. Site 1, which is non-canonical, binds nucleotide tightly but is not hydrolytic. Recently, based on kinetic arguments, it was suggested that this site remains closed for several gating cycles. To investigate movements at site 1 by an independent technique, we studied changes in thermodynamic coupling between pairs of residues on opposite sides of this site. The chosen targets are likely to interact based on both phylogenetic analysis and closeness on structural models. First, we mutated T460 in NBD1 and L1353 in NBD2 (the corresponding site-2 residues become energetically coupled as channels open). Mutation T460S accelerated closure in hydrolytic conditions and in the nonhydrolytic K1250R background; mutation L1353M did not affect these rates. Analysis of the double mutant showed additive effects of mutations, suggesting that energetic coupling between the two residues remains unchanged during the gating cycle. We next investigated pairs 460\u20131348 and 460\u20131375. Although both mutations H1348A and H1375A produced dramatic changes in hydrolytic and nonhydrolytic channel closing rates, in the corresponding double mutants these changes proved mostly additive with those caused by mutation T460S, suggesting little change in energetic coupling between either positions 460\u20131348 or positions 460\u20131375 during gating. These results provide independent support for a gating model in which ATP-bound composite site 1 remains closed throughout the gating cycle.<\/jats:p>","DOI":"10.1085\/jgp.201110608","type":"journal-article","created":{"date-parts":[[2011,5,17]],"date-time":"2011-05-17T02:00:21Z","timestamp":1305597621000},"page":"549-562","update-policy":"http:\/\/dx.doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Mutant cycles at CFTR\u2019s non-canonical ATP-binding site support little interface separation during gating"],"prefix":"10.1085","volume":"137","author":[{"given":"Andras","family":"Szollosi","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry, Semmelweis University, Budapest H-1094, Hungary 1"}]},{"given":"Daniella R.","family":"Muallem","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, England, UK 2"}]},{"given":"L\u00e1szl\u00f3","family":"Csan\u00e1dy","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Semmelweis University, Budapest H-1094, Hungary 1"}]},{"given":"Paola","family":"Vergani","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, England, UK 2"}]}],"member":"291","published-online":{"date-parts":[[2011,5,16]]},"reference":[{"key":"2023072922475546500_bib1","article-title":"Molecular Biology of the Cell","author":"Alberts","year":"2002","edition":"Fourth edition"},{"key":"2023072922475546500_bib2","doi-asserted-by":"publisher","first-page":"15419","DOI":"10.1074\/jbc.M111713200","article-title":"The first nucleotide binding domain of cystic fibrosis transmembrane conductance regulator is a site of stable nucleotide interaction, whereas the second is a site of rapid turnover","volume":"277","author":"Aleksandrov","year":"2002","journal-title":"J. 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