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Papers In Press, published online ahead of print November 5, 2001
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242
Corresponding Author: mjwelsh{at}blue.weeg.uiowa.edu
The CFTR Cl- channel is an ATP-binding cassette (ABC) transporter that contains conserved nucleotide-binding domains (NBDs). In CFTR, the NBDs bind and hydrolyze ATP to open and close the channel. Crystal structures of related NBDs suggest a structural model with an important signaling role for a (gamma)-phosphate linker peptide that couples bound nucleotide to movement of an a-helical subdomain. We mutated two residues in CFTR which the structural model predicts would uncouple effects of nucleotide binding from movement of the (alpha)-helical subdomain: Gln493 and Gln1291 that may directly connect the ATP (gamma)-phosphate to the (gamma)-phosphate linker, and Asn505 and Asn1303 that may form hydrogen bonds that stabilize the linker. In NBD1, Q493A reduced the frequency of channel opening, suggesting a role for this residue in coupling ATP binding to channel opening. In contrast, N505C increased the frequency of channel opening, consistent with a role for Asn505 in stabilizing the inactive state of the NBD. In NBD2, Q1291A decreased the effects of pyrophosphate without altering other functions. Mutations of Asn1303 decreased the rate of channel opening and closing, suggesting an important role for NBD2 in controlling channel burst duration. These findings are consistent with both the bacterial NBD structural model and gating models for CFTR. Our results extend models of nucleotide-induced structural changes from bacterial NBDs to a functional mammalian ABC transporter.
J. Biol. Chem, 10.1074/jbc.M109539200
Submitted on October 2, 2001
Revised on November 2, 2001
Accepted on November 4, 2001
Mutations that change the position of the putative
-phosphate linker in the nucleotide binding domains of CFTR alter channel gating
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