ABCG2 p.Tyr459Cys
| Predicted by SNAP2: | A: D (66%), C: D (59%), D: D (91%), E: D (75%), F: N (53%), G: D (75%), H: N (53%), I: D (63%), K: D (75%), L: D (66%), M: D (75%), N: D (63%), P: D (91%), Q: D (66%), R: D (59%), S: D (63%), T: D (66%), V: D (63%), W: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: N, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, |
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[hide] Sequence mutations of the substrate binding pocket... Oncol Rep. 2013 May;29(5):1697-700. doi: 10.3892/or.2013.2324. Epub 2013 Mar 5. Zoernig I, Ziegelmeier C, Lahrmann B, Grabe N, Jager D, Halama N
Sequence mutations of the substrate binding pocket of stem cell factor and multidrug resistance protein ABCG2 in renal cell cancer: a possible link to treatment resistance.
Oncol Rep. 2013 May;29(5):1697-700. doi: 10.3892/or.2013.2324. Epub 2013 Mar 5., [PMID:23467750]
Abstract [show]
ABCG2 is a multidrug cellular transport protein that is associated with resistance to certain treatments in patients, particularly anticancer treatment. The tumor-protective properties of ABCG2 expression are reported to be a feature of a subset of stem cell-like tumor cells. While protection against chemotherapy has been well analyzed, the role of ABCG2 in the treatment with tyrosine kinase inhibitors is only partially understood. Tyrosine kinase inhibitors are currently the main treatment option in irresectable renal cell carcinomas. To investigate possible underlying sequence variations in the ABCG2 gene with relevance to the functional properties of the protein, 36 patient samples were analyzed. Using sequence analysis and single-nucleotide polymorphism databases, sequence variations in the highly conserved domains of the binding pocket of ABCG2 were analyzed. The resulting variations were used for computational protein prediction algorithms to identify conformational alterations. A relevant shift from A to G at position 1376 (resulting in Y-->C at 459 aa) was identified and found to be present in 8.3% of the patients. These patients are currently in follow-up after resection, thus, further analysis will reveal whether this mutation has relevance to treatment efficacy.
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No. Sentence Comment
92 Our data shows a mutation resulting in Y459C in the intracellular domain 1a (ICD1a).
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ABCG2 p.Tyr459Cys 23467750:92:39
status: NEW[hide] Mutations of the central tyrosines of putative cho... Biochim Biophys Acta. 2015 Feb;1848(2):477-87. doi: 10.1016/j.bbamem.2014.11.006. Epub 2014 Nov 14. Gal Z, Hegedus C, Szakacs G, Varadi A, Sarkadi B, Ozvegy-Laczka C
Mutations of the central tyrosines of putative cholesterol recognition amino acid consensus (CRAC) sequences modify folding, activity, and sterol-sensing of the human ABCG2 multidrug transporter.
Biochim Biophys Acta. 2015 Feb;1848(2):477-87. doi: 10.1016/j.bbamem.2014.11.006. Epub 2014 Nov 14., [PMID:25445676]
Abstract [show]
Human ABCG2 is a plasma membrane glycoprotein causing multidrug resistance in cancer. Membrane cholesterol and bile acids are efficient regulators of ABCG2 function, while the molecular nature of the sterol-sensing sites has not been elucidated. The cholesterol recognition amino acid consensus (CRAC, L/V-(X)(1-5)-Y-(X)(1-5)-R/K) sequence is one of the conserved motifs involved in cholesterol binding in several proteins. We have identified five potential CRAC motifs in the transmembrane domain of the human ABCG2 protein. In order to define their roles in sterol-sensing, the central tyrosines of these CRACs (Y413, 459, 469, 570 and 645) were mutated to S or F and the mutants were expressed both in insect and mammalian cells. We found that mutation in Y459 prevented protein expression; the Y469S and Y645S mutants lost their activity; while the Y570S, Y469F, and Y645F mutants retained function as well as cholesterol and bile acid sensitivity. We found that in the case of the Y413S mutant, drug transport was efficient, while modulation of the ATPase activity by cholesterol and bile acids was significantly altered. We suggest that the Y413 residue within a putative CRAC motif has a role in sterol-sensing and the ATPase/drug transport coupling in the ABCG2 multidrug transporter.
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224 Recently, the Y459C heterozygous mutation was reported to occur in patients with renal cancer [38].
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ABCG2 p.Tyr459Cys 25445676:224:14
status: NEW