ABCC7 p.Asn505Ala
| Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (91%), E: D (91%), F: D (91%), G: D (85%), H: D (85%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), P: D (91%), Q: D (85%), R: D (91%), S: D (85%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Mutations that change the position of the putative... J Biol Chem. 2002 Jan 18;277(3):2125-31. Berger AL, Ikuma M, Hunt JF, Thomas PJ, Welsh MJ
Mutations that change the position of the putative gamma-phosphate linker in the nucleotide binding domains of CFTR alter channel gating.
J Biol Chem. 2002 Jan 18;277(3):2125-31., 2002-01-18 [PMID:11788611]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is an ATP-binding cassette 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 alpha-helical subdomain. We mutated two residues in CFTR that the structural model predicts will uncouple effects of nucleotide binding from movement of the alpha-helical subdomain. These residues are Gln-493 and Gln-1291, which may directly connect the ATP gamma-phosphate to the gamma-phosphate linker, and residues Asn-505 and Asn-1303, which 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 Asn-505 in stabilizing the inactive state of the NBD. In NBD2, Q1291A decreased the effects of pyrophosphate without altering other functions. Mutations of Asn-1303 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 ATP-binding cassette transporter.
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No. Sentence Comment
138 CFTR-N505A had gating kinetics similar to those of wild type; presumably the introduced Ala did not disrupt the structure to the same extent as when Cys was substituted for Asn.
X
ABCC7 p.Asn505Ala 11788611:138:5
status: NEW140 Inhibition by ADP, stimulation by PPi, and the EC50 for ATP stimulation were not altered by the N505C or N505A mutations (data not shown).
X
ABCC7 p.Asn505Ala 11788611:140:105
status: NEW167 B, data from multiple patches. Asterisk indicates p Ͻ 0.05 compared with wild type CFTR; n ϭ 4 for CFTR-N505A and 6 for CFTR-N505C.
X
ABCC7 p.Asn505Ala 11788611:167:116
status: NEW