ABCG2 p.Ala632Val
| Predicted by SNAP2: | C: D (59%), D: D (85%), E: D (91%), F: D (75%), G: N (57%), H: D (85%), I: D (66%), K: D (91%), L: D (75%), M: D (66%), N: D (75%), P: D (91%), Q: D (85%), R: D (85%), S: N (57%), T: D (75%), V: N (53%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Dominant-negative inhibition of breast cancer resi... Int J Cancer. 2002 Feb 10;97(5):626-30. Kage K, Tsukahara S, Sugiyama T, Asada S, Ishikawa E, Tsuruo T, Sugimoto Y
Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization.
Int J Cancer. 2002 Feb 10;97(5):626-30., 2002-02-10 [PMID:11807788]
Abstract [show]
Breast cancer resistance protein (BCRP) is a half-molecule ABC transporter highly expressed in mitoxantrone-resistant cells. In our study we established PA317 transfectants expressing Myc-tagged BCRP (MycBCRP) or HA-tagged BCRP (HABCRP). The exogenous BCRP protein migrated as a 70-kDa protein in SDS-PAGE under reducing condition, but migrated as a 140-kDa complex in the absence of reducing agents. The 140-kDa BCRP complex was heat-stable but dissociated into 70-kDa BCRP with the addition of 2-mercaptoethanol. The 140-kDa BCRP complex was immunoprecipitated with anti-Myc antibody from the lysates of PA317 cells double-transfected with MycBCRP and HABCRP. The 140-kDa complex reacted with anti-HA and anti-BCRP antibodies and after the addition of reducing agents, a 70-kDa protein reacting with anti-Myc, anti-HA and anti-BCRP antibodies was detected. These results clearly indicate that BCRP forms a homodimer bridged by disulfide bonds. To assess the possible dominant-negative inhibition of BCRP drug efflux pump, various mutant BCRP cDNAs were isolated by PCR mutagenesis. First, mutant BCRP cDNAs were introduced to parental PA317 cells and tested for their function as drug-resistance genes. Next, inactive BCRP cDNA clones were introduced to MycBCRP-transfected cells and tested for the ability to lower drug resistance. Among the 8 inactive mutant cDNA clones tested, HABCRP cDNA clone 15 with an amino acid change from Leu to Pro at residue 554 in the fifth transmembrane domain of BCRP partially reversed the drug resistance of MycBCRP-transfected cells. These results suggest that homodimer formation is essential for BCRP drug resistance, implicating this dominant-negative inhibition as a new strategy to circumvent drug resistance.
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No. Sentence Comment
151 to Ala and Tyr-605 to Cys), HABCRP-37 (Thr-82 to Ala) or HABCRP-74 (Ser-25 to Pro, Arg-309 to Gly and Ala-632 to Val), also expressed mutant BCRP protein, but cells transfected with HABCRP-86 (Lys-86 to Ile) did not express BCRP protein and therefore exhibited no drug resistance.
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ABCG2 p.Ala632Val 11807788:151:102
status: VERIFIED[hide] ATP-binding cassette (ABC) transporters in human m... Physiol Res. 2004;53(3):235-43. Stefkova J, Poledne R, Hubacek JA
ATP-binding cassette (ABC) transporters in human metabolism and diseases.
Physiol Res. 2004;53(3):235-43., [PMID:15209530]
Abstract [show]
The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of substrates including amino acids, lipids, inorganic ions, peptides, saccharides, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but also are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. The typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. Defects in 14 of these transporters cause 13 genetic diseases (cystic fibrosis, Stargardt disease, adrenoleukodystrophy, Tangier disease, etc.). Mutations in three genes affect lipid levels expressively. Mutations in ABCA1 cause severe HDL deficiency syndromes called Tangier disease and familial high-density lipoprotein deficiency, which are characterized by a severe deficiency or absence of high-density lipoprotein in the plasma. Two other ABCG transporters, ABCG5 and ABCG8, mutations of which cause sitosterolemia, have been identified. The affected individuals absorb and retain plant sterols, as well as shellfish sterols.
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No. Sentence Comment
106 The substitution of valine for alanine at amino acid 632 was associated with plasma cholesterol concentrations, but was not consistently associated with any of the other sterols.
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ABCG2 p.Ala632Val 15209530:106:20
status: NEW[hide] ABCMdb: A database for the comparative analysis of... Hum Mutat. 2012 Nov;33(11):1547-56. doi: 10.1002/humu.22138. Epub 2012 Jul 11. Gyimesi G, Borsodi D, Saranko H, Tordai H, Sarkadi B, Hegedus T
ABCMdb: A database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application.
Hum Mutat. 2012 Nov;33(11):1547-56. doi: 10.1002/humu.22138. Epub 2012 Jul 11., [PMID:22693078]
Abstract [show]
To overcome the pathological phenomena caused by altered function of ABC (ATP Binding Cassette) proteins, their mechanisms of action are extensively investigated, often involving the design of mutant constructs for experiments. Designing mutagenetic constructs, interpreting the result of mutagenetic experiments, and finding individual genetic variants require an extensive knowledge of previously published mutations. To aid the recapitulation of mutations described in the literature, we set up a database of ABC protein mutations (ABCMdb) extracted from full-text papers using an automatic mining approach. We have also developed a Web application interface to compare mutations in different ABC proteins using sequence alignments and to interactively map the mutations to 3D structural models. Currently our database contains protein mutations published for ABCB1, ABCB11, ABCC1, ABCC6, ABCC7, and the proteins of the ABCG subfamily. The database will be extended to include other members and subfamilies, and to provide information on whether or not a mutation is disease causing, represents a high-incidence polymorphism, or was generated only in vitro. The ABCMdb database should already help to compare the effects of mutations at homologous positions in different ABC proteins, and its interactive tools aim to advance the design of experiments for a wider range of proteins. Hum Mutat 33:1547-1556, 2012. (c) 2012 Wiley Periodicals, Inc.
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No. Sentence Comment
138 There were two cases where the reverse of the mutation was mentioned in the reference paper, such as "A632V" instead of "V632A" (p.Val632Ala), which might indicate a sequence ambiguity.
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ABCG2 p.Ala632Val 22693078:138:102
status: NEW