Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator

Hal A. Lewis, Sean G. Buchanan, Stephen K. Burley, Kris Conners, Mark Dickey, Michael Dorwart, Richard Fowler, Xia Gao, William B. Guggino, Wayne A. Hendrickson, John F. Hunt, Margaret C. Kearins, Don Lorimer, Peter C. Maloney, Kai W. Post, Kanagalaghatta R. Rajashankar, Marc E. Rutter, J. Michael Sauder, Stephanie Shriver, Patrick H. ThibodeauPhilip J. Thomas, Marie Zhang, Xun Zhao, Spencer Emtage

Research output: Contribution to journalArticle

322 Scopus citations

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that functions as a chloride channel. Nucleotide-binding domain 1 (NBD1), one of two ABC domains in CFTR, also contains sites for the predominant CF-causing mutation and, potentially, for regulatory phosphorylation. We have determined crystal structures for mouse NBD1 in unliganded, ADP- and ATP-bound states, with and without phosphorylation. This NBD1 differs from typical ABC domains in having added regulatory segments, a foreshortened subdomain interconnection, and an unusual nucleotide conformation. Moreover, isolated NBD1 has undetectable ATPase activity and its structure is essentially the same independent of ligand state. Phe508, which is commonly deleted in CF, is exposed at a putative NBD1-transmembrane interface. Our results are consistent with a CFTR mechanism, whereby channel gating occurs through ATP binding in an NBD1-NBD2 nucleotide sandwich that forms upon displacement of NBD1 regulatory segments.

Original languageEnglish (US)
Pages (from-to)282-293
Number of pages12
JournalEMBO Journal
Volume23
Issue number2
DOIs
StatePublished - Jan 28 2004

Keywords

  • ABC transporter
  • CFTR
  • Crystal structure
  • NBD1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Lewis, H. A., Buchanan, S. G., Burley, S. K., Conners, K., Dickey, M., Dorwart, M., Fowler, R., Gao, X., Guggino, W. B., Hendrickson, W. A., Hunt, J. F., Kearins, M. C., Lorimer, D., Maloney, P. C., Post, K. W., Rajashankar, K. R., Rutter, M. E., Sauder, J. M., Shriver, S., ... Emtage, S. (2004). Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO Journal, 23(2), 282-293. https://doi.org/10.1038/sj.emboj.7600040