ABCC7 p.Arg518Ala
| Predicted by SNAP2: | A: N (82%), C: N (57%), D: N (66%), E: N (87%), F: D (63%), G: N (66%), H: N (87%), I: N (82%), K: N (97%), L: N (87%), M: N (82%), N: N (93%), P: N (57%), Q: N (93%), S: N (87%), T: N (97%), V: N (82%), W: N (66%), Y: D (59%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: N, W: N, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Identification of molecular determinants that modu... Cell Biochem Biophys. 2005;42(1):41-53. Tsigelny I, Hotchko M, Yuan JX, Keller SH
Identification of molecular determinants that modulate trafficking of DeltaF508 CFTR, the mutant ABC transporter associated with cystic fibrosis.
Cell Biochem Biophys. 2005;42(1):41-53., [PMID:15673927]
Abstract [show]
Cystic fibrosis is a life-shortening inherited disorder associated primarily with a three-base in frame deletion that eliminates Phe508 in the ABC transporter, cystic fibrosis transmembrane conductance regulator (CFTR). Mutant CFTR, designated deltaF508 CFTR, is misprocessed and retained intracellularly. It is unclear what causes the trafficking impairment despite extensive investigative effort and the disease's prevalence. We hypothesize that the trafficking impairment is mediated by "receptors" of the cellular trafficking machinery that at three sequential "trafficking checkpoints" govern (1) exit from the endoplasmic reticulum (ER), (2) Golgi to the ER retrieval, and (3) targeting from post-Golgi compartments to lysosomes. We propose that, because of the Phe508 deletion and polypeptide misfolding: (1) a forward-directing signal recognized by the sec24 component of the COPII complex that mediates ER exit is eliminated; (2) a basic amino acid signal recognized by the COPI machinery involved in Golgi to ER retrieval becomes activated; and (3) a tyrosine-based sorting signal that targets to the lysosomes likewise becomes activated. We employed recently reported crystal structures of CFTR nucleotide binding domain 1 and sec24 in computational docking models to identify the most plausible CFTR-sec24 recognition domain. Site-directed mutagenesis and heterologous expression were also used to identify amino acid sequences that operate in Golgi to ER and post-Golgi to lysosome targeting. The importance of considering a multiple checkpoint model for trafficking is that rationale design of pharmaceutical interventions would require abrogation of all major checkpoints to deliver deltaF508 CFTR to the cell surface.
Comments [show]
None has been submitted yet.
No. Sentence Comment
172 The putative basic amino acid and tyrosine-based trafficking signals were altered by site-directed mutagenesis to eliminate the canonical trafficking signal sequences at the 516-520 site by changing the Tyr-517 and Arg-518 residues to Ala (this variant designated Y517A:R518A ∆F508 CFTR).
X
ABCC7 p.Arg518Ala 15673927:172:215
status: NEW