ABCC7 p.Glu504Gln
| ClinVar: |
c.1510G>T
,
p.Glu504*
?
, not provided
c.1510G>C , p.Glu504Gln ? , not provided |
| CF databases: |
c.1510G>C
,
p.Glu504Gln
(CFTR1)
?
,
|
| Predicted by SNAP2: | A: D (85%), C: D (91%), D: D (66%), F: D (95%), G: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (95%), M: D (95%), N: D (85%), P: D (95%), Q: N (53%), R: D (95%), S: D (85%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] The conserved glutamate residue adjacent to the Wa... J Biol Chem. 2003 Nov 21;278(47):47002-8. Epub 2003 Sep 10. Orelle C, Dalmas O, Gros P, Di Pietro A, Jault JM
The conserved glutamate residue adjacent to the Walker-B motif is the catalytic base for ATP hydrolysis in the ATP-binding cassette transporter BmrA.
J Biol Chem. 2003 Nov 21;278(47):47002-8. Epub 2003 Sep 10., [PMID:12968023]
Abstract [show]
ATP-binding cassette (ABC) proteins constitute one of the widest families in all organisms, whose P-glycoprotein involved in resistance of cancer cells to chemotherapy is an archetype member. Although three-dimensional structures of several nucleotide-binding domains of ABC proteins are now available, the catalytic mechanism triggering the functioning of these proteins still remains elusive. In particular, it has been postulated that ATP hydrolysis proceeds via an acid-base mechanism catalyzed by the Glu residue adjacent to the Walker-B motif (Geourjon, C., Orelle, C., Steinfels, E., Blanchet, C., Deleage, G., Di Pietro, A., and Jault, J. M. (2001) Trends Biochem. Sci. 26, 539-544), but the involvement of such residue as the catalytic base in ABC transporters was recently questioned (Sauna, Z. E., Muller, M., Peng, X. H., and Ambudkar, S. V. (2002) Biochemistry, 41, 13989-14000). The equivalent glutamate residue (Glu504) of a half-ABC transporter involved in multidrug resistance in Bacillus subtilis, BmrA (formerly known as YvcC), was therefore mutated to Asp, Ala, Gln, Ser, and Cys residues. All these mutants were fully devoid of ATPase activity, yet they showed a high level of vanadate-independent trapping of 8-N3-alpha-32P-labeled nucleotide(s), following preincubation with 8-N3-[alpha-32P]ATP. However, and in contrast to the wild-type enzyme, the use of 8-N3-[gamma-32P]ATP unequivocally showed that all the mutants trapped exclusively the triphosphate form of the analogue, suggesting that they were not able to perform even a single hydrolytic turnover. These results demonstrate that Glu504 is the catalytic base for ATP hydrolysis in BmrA, and it is proposed that equivalent glutamate residues in other ABC transporters play the same role.
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No. Sentence Comment
39 To screen for positive clones, oligonucleotides were designed to introduce simultaneously a new AatII restriction site, without modifying the protein sequence, and the desired mutation: E504A, GTCGAGACTTGACGTC- GCTGCATCGAGCATAAG; E504Q, GTCGAGACTTGACGTCGCTTG- ATCGAGCATAAGA; E504C, GTCGAGACTTGACGTCGCACAATC- GAG CATAAGA; E504D, GTCGAGACTTGACGTCGCATCATCGAGC- ATAAG; and E504S, GTCGAGACTTGACGTCGCTGAATCGAGCATA- AGAA.
X
ABCC7 p.Glu504Gln 12968023:39:230
status: NEW78 The two other mutants, namely E504Q and especially E504A, might have an impaired ability to bind the ATP analogue, as further confirmed by increasing its concen- FIG. 1.
X
ABCC7 p.Glu504Gln 12968023:78:30
status: NEW109 Lane 1, wild-type BmrA; lane 2, E504A mutant; lane 3, E504C mutant; lane 4, E504D mutant; lane 5, E504Q mutant; and lane 6, E504S mutant.
X
ABCC7 p.Glu504Gln 12968023:109:98
status: NEW112 BmrA protein ATPase activity Hoechst transport nmol ATP hydrolyzed per min/mg protein Wild-type 6,500 Ϯ 500 ϩϩϩ E504D 0 Ϯ 5 - E504A 0 Ϯ 5 - E504C 0 Ϯ 5 ND E504Q 0 Ϯ 5 ND E504S 0 Ϯ 5 ND FIG. 3.
X
ABCC7 p.Glu504Gln 12968023:112:197
status: NEW169 However, addition of ATP in the presence of Mg2ϩ destroyed the ring-shaped structure not only for the wild-type BmrA but also for the E504Q mutant.
X
ABCC7 p.Glu504Gln 12968023:169:140
status: NEW[hide] Modeling of nucleotide binding domains of ABC tran... J Bioenerg Biomembr. 1997 Oct;29(5):503-24. Bianchet MA, Ko YH, Amzel LM, Pedersen PL
Modeling of nucleotide binding domains of ABC transporter proteins based on a F1-ATPase/recA topology: structural model of the nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator (CFTR).
J Bioenerg Biomembr. 1997 Oct;29(5):503-24., [PMID:9511935]
Abstract [show]
Members of the ABC transporter superfamily contain two nucleotide binding domains. To date, the three dimensional structure of no member of this super-family has been elucidated. To gain structural insight, the known structures of several other nucleotides binding proteins can be used as a framework for modeling these domains. We have modeled both nucleotide binding domains of the protein CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) using the two similar domains of mitochondrial F1-ATPase. The models obtained, provide useful insights into the putative functions of these domains and their possible interaction as well as a rationale for the basis of Cystic Fibrosis causing mutations. First, the two nucleotide binding domains (folds) of CFTR are each predicted to span a 240-250 amino acid sequence rather than the 150-160 amino acid sequence originally proposed. Second, the first nucleotide binding fold, is predicted to catalyze significant rates of ATP hydrolysis as a catalytic base (E504) resides near the y phosphate of ATP. This prediction has been verified experimentally [Ko, Y.H., and Pedersen, P.L. (1995) J. Biol. Chem. 268, 24330-24338], providing support for the model. In contrast, the second nucleotide binding fold is predicted at best to be a weak ATPase as the glutamic acid residue is replaced with a glutamine. Third, F508, which when deleted causes approximately 70% of all cases of cystic fibrosis, is predicted to lie in a cleft near the nucleotide binding pocket. All other disease causing mutations within the two nucleotide binding domains of CFTR either reside near the Walker A and Walker B consensus motifs in the heart of the nucleotide binding pocket, or in the C motif which lies outside but near the nucleotide binding pocket. Finally, the two nucleotide binding domains of CFTR are predicted to interact, and in one of the two predicted orientations, F508 resides near the interface. This is the first report where both nucleotide binding domains of an ABC transporter and their putative domain-domain interactions have been modeled in three dimensions. The methods and the template used in this work can be used to analyze the structures and function of the nucleotide binding domains of all other members of the ABC transporter super-family.
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None has been submitted yet.
No. Sentence Comment
226 Mutations such as E504Q do cause CF.
X
ABCC7 p.Glu504Gln 9511935:226:18
status: NEW257 Certainly, the disease causing mutation E504Q, and probably the AI507 and AF508 mutations have an effect on the function, position, and in the geometry of the loop that contains E504.
X
ABCC7 p.Glu504Gln 9511935:257:40
status: NEW360 The CFTR NBD1 model that results (Fig. 6) gathers the disease causing mutations in three different clusters: (1) mutations affecting the nucleotide binding pocket and the putative general base: A455E, G458V, E504Q AI507 AF508 P574H; (2) mutations in motif C which are probably related to an interaction with region D: S549[R,N,I] G551[S,D], R553Q; and (3) mutations within or near motif B, L558S, A559T, R560T, Y563N and mutations S492F and G480C.
X
ABCC7 p.Glu504Gln 9511935:360:208
status: NEW[hide] Frontiers in research on cystic fibrosis: understa... J Bioenerg Biomembr. 1997 Oct;29(5):417-27. Ko YH, Pedersen PL
Frontiers in research on cystic fibrosis: understanding its molecular and chemical basis and relationship to the pathogenesis of the disease.
J Bioenerg Biomembr. 1997 Oct;29(5):417-27., [PMID:9511927]
Abstract [show]
In recent years a new family of transport proteins called ABC transporters has emerged. One member of this novel family, called CFTR (cystic fibrosis transmembrane conductance regulator), has received special attention because of its association with the disease cystic fibrosis (CF). This is an inherited disorder affecting about 1 in 2000 Caucasians by impairing epithelial ion transport, particularly that of chloride. Death may occur in severe cases because of chronic lung infections, especially by Pseudomonas aeruginosa, which cause a slow decline in pulmonary function. The prospects of ameliorating the symptoms of CF and even curing the disease were greatly heightened in 1989 following the cloning of the CFTR gene and the discovery that the mutation (deltaF508), which causes most cases of CF, is localized within a putative ATP binding/ATP hydrolysis domain. The purpose of this introductory review in this minireview series is to summarize what we and others have learned during the past eight years about the structure and function of the first nucleotide binding domain (NBF1 or NBD1) of the CFTR protein and the effect thereon of disease-causing mutations. The relationship of these new findings to the pathogenesis of CF is also discussed.
Comments [show]
None has been submitted yet.
No. Sentence Comment
93 Consistent with the predicted functional importance of E504 as a catalytic base (see Discussion above), it will be noted that the inherited mutation E504Q also causes cystic fibrosis.
X
ABCC7 p.Glu504Gln 9511927:93:149
status: NEW[hide] Two new mutations detected by single-strand confor... Hum Genet. 1993 Mar;91(1):63-5. Ivaschenko TE, Baranov VS, Dean M
Two new mutations detected by single-strand conformation polymorphism analysis in cystic fibrosis from Russia.
Hum Genet. 1993 Mar;91(1):63-5., [PMID:7681034]
Abstract [show]
Single-strand conformation polymorphism (SSCP) analysis followed by direct sequencing of exons containing ATP-binding domains of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was performed on 80 Russian DNA samples. Two new alterations--S1196X (exon 19) and W1282R (exon 20)--and two novel polymorphisms--1525-61 (intron 9) and 1716+12 T-C (intron 10)--were identified. Mutation S1196X changes a TCA codon to TGA and destroys an EcoRI site. Alteration W1282R results from a T-to-C change at position 3976. It was found in one Russian patient and creates an AciI site; however, it is unclear whether this is a disease-causing mutation or a polymorphism. Polymorphism 1525-61 results from an A-to-G change. Alteration 1716+12 T-C was found in a Moldovian patient and creates a new MaeII site. It is not known whether this alteration affects the splicing of the mRNA. The previously described A4002G polymorphism was encountered in approximately 9% of Russian CF chromosomes. In addition, we have found the previously described 3732delA mutation in 7 CF chromosomes, making it the second (after delta F508) most frequent mutation in the Russian population.
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None has been submitted yet.
No. Sentence Comment
18 Actually only three new CF mutations have been detected in this country so far - 3821delT (White et al. 1991), 1677delTA (Ivaschenko et al. 1991), and E504Q (Baranov et al. 1991b).
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ABCC7 p.Glu504Gln 7681034:18:151
status: NEW19 Two of them (1677delTA and E504Q) were found by chance as a by-product of exon 10 analysis for AF508 mutation in CF high-risk families requesting prenatal diagnosis.
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ABCC7 p.Glu504Gln 7681034:19:27
status: NEW