ABCC7 p.Tyr512Ala
| Predicted by SNAP2: | A: D (80%), C: D (71%), D: D (91%), E: D (91%), F: D (59%), G: D (91%), H: N (53%), I: D (75%), K: D (91%), L: D (53%), M: N (61%), N: D (85%), P: D (91%), Q: D (80%), R: D (91%), S: D (85%), T: D (85%), V: D (80%), W: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] CLC-0 and CFTR: chloride channels evolved from tra... Physiol Rev. 2008 Apr;88(2):351-87. Chen TY, Hwang TC
CLC-0 and CFTR: chloride channels evolved from transporters.
Physiol Rev. 2008 Apr;88(2):351-87., [PMID:18391167]
Abstract [show]
CLC-0 and cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels play important roles in Cl(-) transport across cell membranes. These two proteins belong to, respectively, the CLC and ABC transport protein families whose members encompass both ion channels and transporters. Defective function of members in these two protein families causes various hereditary human diseases. Ion channels and transporters were traditionally viewed as distinct entities in membrane transport physiology, but recent discoveries have blurred the line between these two classes of membrane transport proteins. CLC-0 and CFTR can be considered operationally as ligand-gated channels, though binding of the activating ligands appears to be coupled to an irreversible gating cycle driven by an input of free energy. High-resolution crystallographic structures of bacterial CLC proteins and ABC transporters have led us to a better understanding of the gating properties for CLC and CFTR Cl(-) channels. Furthermore, the joined force between structural and functional studies of these two protein families has offered a unique opportunity to peek into the evolutionary link between ion channels and transporters. A promising byproduct of this exercise is a deeper mechanistic insight into how different transport proteins work at a fundamental level.
Comments [show]
None has been submitted yet.
No. Sentence Comment
410 However, the corresponding mutation of Y512A in CLC-0 is almost without functional consequence (4).
X
ABCC7 p.Tyr512Ala 18391167:410:39
status: NEW[hide] Phosphorylation of cystic fibrosis transmembrane c... Amino Acids. 2013 Dec;45(6):1423-9. doi: 10.1007/s00726-013-1613-y. Epub 2013 Nov 1. Cesaro L, Marin O, Venerando A, Donella-Deana A, Pinna LA
Phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) serine-511 by the combined action of tyrosine kinases and CK2: the implication of tyrosine-512 and phenylalanine-508.
Amino Acids. 2013 Dec;45(6):1423-9. doi: 10.1007/s00726-013-1613-y. Epub 2013 Nov 1., [PMID:24178769]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) harbors, close to Phe-508, whose deletion is the commonest cause of cystic fibrosis, a conserved potential CK2 phospho-acceptor site (Ser511), which however is not susceptible to phosphorylation by CK2. To shed light on this apparent paradox, a series of systematically substituted peptides encompassing Ser511 were assayed for their ability to be phosphorylated. The main outcomes of our study are the following: (a) Tyr512 plays a prominent role as a negative determinant as its replacement by Ala restores Ser511 phosphorylation by CK2; (b) an even more pronounced phosphorylation of Ser511 is promoted if Tyr512 is replaced by phospho-tyrosine instead of alanine; (c) Tyr512 and, to a lesser extent, Tyr515 are readily phosphorylated by Lyn, a protein tyrosine kinase of the Src family, in a manner which is enhanced by the concomitant Phe508 deletion. Collectively taken, our data, in conjunction with the notion that Tyr515 is phosphorylated in vivo, disclose the possibility that CFTR Ser511 can be phosphorylated by the combined action of tyrosine kinases and CK2 and disclose a new mechanism of hierarchical phosphorylation where the role of the priming kinase is that of removing negative determinant(s).
Comments [show]
None has been submitted yet.
No. Sentence Comment
49 As shown in Table 1 neither the parent peptide nor any of the substituted peptides were significantly phosphorylated by CK2, with the notable exception of the peptide in which Tyr512 was replaced by alanine (peptide 4).
X
ABCC7 p.Tyr512Ala 24178769:49:176
status: NEW105 Peptides reproducing the 500-523 sequence of F508delCFTR were synthesized either as such (see legend of Fig. 2) or with Tyr512 replaced by Ala (Y512A) or by phospho-tyrosine (pY512).
X
ABCC7 p.Tyr512Ala 24178769:105:120
status: NEWX
ABCC7 p.Tyr512Ala 24178769:105:144
status: NEW108 Lanes 1, 2 and 3 refer to unsubstituted, Y512A and pY512 peptides, respectively.
X
ABCC7 p.Tyr512Ala 24178769:108:41
status: NEW119 The mechanism of Ser511 phosphorylation outlined here can also provide an explanation for the finding that two CFTR mutants, in which Tyr512 has been replaced by Ala and Asp, respectively, undergo defective maturation with reduced cell surface exposition (Luz et al. 2011).
X
ABCC7 p.Tyr512Ala 24178769:119:134
status: NEW[hide] A "SYDE" effect of hierarchical phosphorylation: p... Cell Mol Life Sci. 2014 Jun;71(12):2193-6. doi: 10.1007/s00018-014-1581-8. Epub 2014 Feb 25. Venerando A, Cesaro L, Marin O, Donella-Deana A, Pinna LA
A "SYDE" effect of hierarchical phosphorylation: possible relevance to the cystic fibrosis basic defect.
Cell Mol Life Sci. 2014 Jun;71(12):2193-6. doi: 10.1007/s00018-014-1581-8. Epub 2014 Feb 25., [PMID:24566881]
Abstract [show]
The motif "SYDE", incorporating the protein kinase CK2 consensus sequence (S-x-x-E) has been found to be phosphorylated at both its serine and tyrosine residues in several proteins. Of special interest is the case of cystic fibrosis Transmembrane-conductance Regulator (CFTR), where this motif is close to the residue (F508), whose deletion is the by far commonest cause of cystic fibrosis. Intriguingly, however, CFTR S511 cannot be phosphorylated by CK2 to any appreciable extent. Using a number of peptide substrates encompassing the CFTR "SYDE" site we have recently shown that: (1) failure of CK2 to phosphorylate the S(511)YDE motif is due to the presence of Y512; (2) CK2 readily phosphorylates S511 if Y512 is replaced by a phospho-tyrosine; (3) the Src family protein tyrosine kinase Lyn phosphorylates Y512 in a manner that is enhanced by the deletion of F508. These data, in conjunction with the recent observation that by inhibiting CK2 the degradation of F508delCFTR is reduced, lead us to hypothesize that the hierarchical phosphorylation of the motif SYDE by the concerted action of protein tyrosine kinases and CK2 is one of the mechanisms that cooperate to the premature degradation of F508delCFTR.
Comments [show]
None has been submitted yet.
No. Sentence Comment
29 A scenario like this would also account for a number of phenomenological observations already available in the literature, notably the defective maturation and reduced cell surface exposition of the CFTR mutant Y512A [20], which, unlike the wild type, is expected to be susceptible to phosphorylation by CK2 at S511 (see Fig. 1) and the increased accumulation of F508delCFTR upon cell treatment with a very specific CK2 inhibitor [21].
X
ABCC7 p.Tyr512Ala 24566881:29:211
status: NEW