CFTR Channel Opening by ATP-driven Tight Dimerization of Its Nucleotide-binding Domains

Overview

Journal Nature

Specialty Science

Date 2005 Feb 25

PMID 15729345

Citations 220

Authors

Paola Vergani

Steve W Lockless

Angus C Nairn

David C Gadsby

Affiliations

Soon will be listed here.

Abstract

ABC (ATP-binding cassette) proteins constitute a large family of membrane proteins that actively transport a broad range of substrates. Cystic fibrosis transmembrane conductance regulator (CFTR), the protein dysfunctional in cystic fibrosis, is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing of the pore have been linked to ATP binding and hydrolysis at CFTR's two nucleotide-binding domains, NBD1 and NBD2 (see, for example, refs 1, 2). Isolated NBDs of prokaryotic ABC proteins dimerize upon binding ATP, and hydrolysis of the ATP causes dimer dissociation. Here, using single-channel recording methods on intact CFTR molecules, we directly follow opening and closing of the channel gates, and relate these occurrences to ATP-mediated events in the NBDs. We find that energetic coupling between two CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The two monitored side chains are independent of each other in closed channels but become coupled as the channels open. The results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide-binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily.

Citing Articles

Structural determinants of protein kinase A essential for CFTR channel activation.

Mihalyi C, Iordanov I, Szollosi A, Csanady L Proc Natl Acad Sci U S A. 2024; 121(46):e2407728121.

PMID: 39495914 PMC: 11573668. DOI: 10.1073/pnas.2407728121.

Genetic Code Expansion for Mechanistic Studies in Ion Channels: An (Un)natural Union of Chemistry and Biology.

Infield D, Schene M, Galpin J, Ahern C Chem Rev. 2024; 124(20):11523-11543.

PMID: 39207057 PMC: 11503617. DOI: 10.1021/acs.chemrev.4c00306.

Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.

Gao X, Yeh H, Yang Z, Fan C, Jiang F, Howard R Nat Commun. 2024; 15(1):6668.

PMID: 39107303 PMC: 11303713. DOI: 10.1038/s41467-024-50641-1.

Coupling enzymatic activity and gating in an ancient TRPM chanzyme and its molecular evolution.

Huang Y, Kumar S, Lee J, Lu W, Du J Nat Struct Mol Biol. 2024; 31(10):1509-1521.

PMID: 38773335 PMC: 11479946. DOI: 10.1038/s41594-024-01316-4.

The ABCF proteins in Escherichia coli individually cope with 'hard-to-translate' nascent peptide sequences.

Chadani Y, Yamanouchi S, Uemura E, Yamasaki K, Niwa T, Ikeda T Nucleic Acids Res. 2024; 52(10):5825-5840.

PMID: 38661232 PMC: 11162784. DOI: 10.1093/nar/gkae309.

References

Davidson A, Chen J . ATP-binding cassette transporters in bacteria. Annu Rev Biochem. 2004; 73:241-68. DOI: 10.1146/annurev.biochem.73.011303.073626. View

Locher K, Lee A, Rees D . The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science. 2002; 296(5570):1091-8. DOI: 10.1126/science.1071142. View

Tombline G, Bartholomew L, Urbatsch I, Senior A . Combined mutation of catalytic glutamate residues in the two nucleotide binding domains of P-glycoprotein generates a conformation that binds ATP and ADP tightly. J Biol Chem. 2004; 279(30):31212-20. DOI: 10.1074/jbc.M404689200. View

Higgins C, Linton K . The ATP switch model for ABC transporters. Nat Struct Mol Biol. 2004; 11(10):918-26. DOI: 10.1038/nsmb836. View

Knowles J . Enzyme-catalyzed phosphoryl transfer reactions. Annu Rev Biochem. 1980; 49:877-919. DOI: 10.1146/annurev.bi.49.070180.004305. View

Serrano L, Horovitz A, Avron B, Bycroft M, Fersht A . Estimating the contribution of engineered surface electrostatic interactions to protein stability by using double-mutant cycles. Biochemistry. 1990; 29(40):9343-52. DOI: 10.1021/bi00492a006. View

Carson M, Travis S, Welsh M . The two nucleotide-binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) have distinct functions in controlling channel activity. J Biol Chem. 1995; 270(4):1711-7. DOI: 10.1074/jbc.270.4.1711. View

Gunderson K, Kopito R . Conformational states of CFTR associated with channel gating: the role ATP binding and hydrolysis. Cell. 1995; 82(2):231-9. DOI: 10.1016/0092-8674(95)90310-0. View

Bakos E, Klein I, Welker E, Szabo K, Muller M, Sarkadi B . Characterization of the human multidrug resistance protein containing mutations in the ATP-binding cassette signature region. Biochem J. 1997; 323 ( Pt 3):777-83. PMC: 1218382. DOI: 10.1042/bj3230777. View

10.

Hung L, Wang I, NIKAIDO K, Liu P, AMES G, Kim S . Crystal structure of the ATP-binding subunit of an ABC transporter. Nature. 1999; 396(6712):703-7. DOI: 10.1038/25393. View

11.

Horn C, Bremer E, Schmitt L . Nucleotide dependent monomer/dimer equilibrium of OpuAA, the nucleotide-binding protein of the osmotically regulated ABC transporter OpuA from Bacillus subtilis. J Mol Biol. 2003; 334(3):403-19. DOI: 10.1016/j.jmb.2003.09.079. View

12.

Verdon G, Albers S, van Oosterwijk N, Dijkstra B, Driessen A, Thunnissen A . Formation of the productive ATP-Mg2+-bound dimer of GlcV, an ABC-ATPase from Sulfolobus solfataricus. J Mol Biol. 2003; 334(2):255-67. DOI: 10.1016/j.jmb.2003.08.065. View

13.

Chen J, Lu G, Lin J, Davidson A, Quiocho F . A tweezers-like motion of the ATP-binding cassette dimer in an ABC transport cycle. Mol Cell. 2003; 12(3):651-61. DOI: 10.1016/j.molcel.2003.08.004. View

14.

Basso C, Vergani P, Nairn A, Gadsby D . Prolonged nonhydrolytic interaction of nucleotide with CFTR's NH2-terminal nucleotide binding domain and its role in channel gating. J Gen Physiol. 2003; 122(3):333-48. PMC: 2234483. DOI: 10.1085/jgp.200308798. View

15.

Janas E, Hofacker M, Chen M, Gompf S, van der Does C, Tampe R . The ATP hydrolysis cycle of the nucleotide-binding domain of the mitochondrial ATP-binding cassette transporter Mdl1p. J Biol Chem. 2003; 278(29):26862-9. DOI: 10.1074/jbc.M301227200. View

16.

Verdon G, Albers S, Dijkstra B, Driessen A, Thunnissen A . Crystal structures of the ATPase subunit of the glucose ABC transporter from Sulfolobus solfataricus: nucleotide-free and nucleotide-bound conformations. J Mol Biol. 2003; 330(2):343-58. DOI: 10.1016/s0022-2836(03)00575-8. View

17.

Hopfner K, Tainer J . Rad50/SMC proteins and ABC transporters: unifying concepts from high-resolution structures. Curr Opin Struct Biol. 2003; 13(2):249-55. DOI: 10.1016/s0959-440x(03)00037-x. View

18.

Vergani P, Nairn A, Gadsby D . On the mechanism of MgATP-dependent gating of CFTR Cl- channels. J Gen Physiol. 2003; 121(1):17-36. PMC: 2217317. DOI: 10.1085/jgp.20028673. View

19.

Smith P, Karpowich N, Millen L, Moody J, Rosen J, Thomas P . ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol Cell. 2002; 10(1):139-49. PMC: 3516284. DOI: 10.1016/s1097-2765(02)00576-2. View

20.

Moody J, Millen L, Binns D, Hunt J, Thomas P . Cooperative, ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters. J Biol Chem. 2002; 277(24):21111-4. PMC: 3516282. DOI: 10.1074/jbc.C200228200. View