ABCC7 p.Asn900Gln
| ClinVar: |
c.2700T>A
,
p.Asn900Lys
D
, Pathogenic
|
| CF databases: |
c.2699A>C
,
p.Asn900Thr
(CFTR1)
?
, Asymptomatic subject
|
| Predicted by SNAP2: | A: N (66%), C: D (53%), D: N (53%), E: N (66%), F: D (71%), G: N (61%), H: N (66%), I: D (59%), K: N (66%), L: N (53%), M: D (53%), P: D (53%), Q: N (66%), R: N (53%), S: N (72%), T: N (78%), V: N (53%), W: D (80%), Y: D (75%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Most F508del-CFTR is targeted to degradation at an... Mol Cell Biol. 2005 Jun;25(12):5242-52. Farinha CM, Amaral MD
Most F508del-CFTR is targeted to degradation at an early folding checkpoint and independently of calnexin.
Mol Cell Biol. 2005 Jun;25(12):5242-52., [PMID:15923638]
Abstract [show]
Biosynthesis and folding of multidomain transmembrane proteins is a complex process. Structural fidelity is monitored by endoplasmic reticulum (ER) quality control involving the molecular chaperone calnexin. Retained misfolded proteins undergo ER-associated degradation (ERAD) through the ubiquitin-proteasome pathway. Our data show that the major degradation pathway of the cystic fibrosis transmembrane conductance regulator (CFTR) with F508del (the most frequent mutation found in patients with the genetic disease cystic fibrosis) from the ER is independent of calnexin. Moreover, our results demonstrate that inhibition of mannose-processing enzymes, unlike most substrate glycoproteins, does not stabilize F508del-CFTR, although wild-type (wt) CFTR is drastically stabilized under the same conditions. Together, our data support a novel model by which wt and F508del-CFTR undergo ERAD from two distinct checkpoints, the mutant being disposed of independently of N-glycosidic residues and calnexin, probably by the Hsc70/Hsp70 machinery, and wt CFTR undergoing glycan-mediated ERAD.
Comments [show]
None has been submitted yet.
No. Sentence Comment
208 As the N-glyconjugate is attached to asparagine residues 894 and 900 of CFTR, we replaced both these residues by either glutamine (N894Q and N900Q) or alanine (N894A and N900A) residues and studied the CFTR turnover of the resulting proteins on wt and F508del backgrounds when stably expressed in BHK cells as above.
X
ABCC7 p.Asn900Gln 15923638:208:141
status: NEW219 BHK cells stably expressing wt CFTR (A, lanes 1 to 5), N894A-N900A (WAA) (A, lanes 6 to 10), N894Q-N900Q (WQQ) (A, lanes 11 to 15), F508del-CFTR (B, lanes 1 to 5), F508del-N894A-N900A (FAA) (B, lanes 6 to 10), or F508del-N894Q-N900Q CFTR (FQQ) (B, lanes 11 to 15) were pulse-labeled and chased as before (Fig. 2) for 0 h (lanes 1, 6, and 11), 0.5 h (lanes 2, 7, and 12), 1 h (lanes 3, 8, and 13), 2 h (lanes 4, 9, and 14), and 3 h (lanes 5, 10, and 15).
X
ABCC7 p.Asn900Gln 15923638:219:99
status: NEWX
ABCC7 p.Asn900Gln 15923638:219:227
status: NEW284 Asparagine residues at positions 894 and 900 were replaced by either two alanines (N894A and N900A) or two glutamines (N894Q and N900Q).
X
ABCC7 p.Asn900Gln 15923638:284:129
status: NEW