ABCB1 p.Ser644Arg
| Predicted by SNAP2: | A: N (82%), C: D (53%), D: N (78%), E: N (87%), F: N (61%), G: N (78%), H: N (78%), I: N (66%), K: N (87%), L: N (72%), M: N (78%), N: N (87%), P: N (72%), Q: N (87%), R: N (82%), T: N (87%), V: N (78%), W: D (71%), Y: D (66%), |
| 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, N: N, P: N, Q: N, R: N, T: N, V: N, W: N, Y: N, |
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[hide] A rare transporter associated with antigen process... Clin Cancer Res. 2005 May 15;11(10):3614-23. Yang T, Lapinski PE, Zhao H, Zhou Q, Zhang H, Raghavan M, Liu Y, Zheng P
A rare transporter associated with antigen processing polymorphism overpresented in HLAlow colon cancer reveals the functional significance of the signature domain in antigen processing.
Clin Cancer Res. 2005 May 15;11(10):3614-23., [PMID:15897556]
Abstract [show]
Transporter associated with antigen processing (TAP), a member of the ATP-binding cassette transporter superfamily, is composed of two integral membrane proteins, TAP-1 and TAP-2. Each subunit has a C-terminal nucleotide-binding domain that binds and hydrolyzes ATP to energize peptide translocation across the endoplasmic reticulum membrane. A motif comprising the sequence LSGGQ (called the signature motif) and the amino acid that is immediately C-terminal to this motif are highly conserved in the nucleotide-binding domains of ATP-binding cassette transporters. To search for natural variants of TAP-1 with alterations in or near the signature motif, we sequenced the TAP-1 exon 10 amplified from 103 human colon cancer samples. We found a rare TAP-1 allele with an R>Q alteration at a residue immediately C-terminal to the signature motif (R648) that occurred 17.5 times more frequently in colon cancers with down-regulated surface class I MHC than those with normal MHC levels (P = 0.01). Functional analysis revealed that the Q648 variant had significantly reduced peptide translocation activity compared with TAP-1 (R648). In addition, we found that mutations S644R, G645R, G646S, and G646D interfered with TAP-1 activity. TAP-1 G646D, which showed the most severe defect, resided normally in the endoplasmic reticulum and associated with the peptide loading complex, but failed to transport peptide across the endoplasmic reticulum membrane. Thus, a TAP-1 polymorphism adjacent to the signature motif may be a contributing factor for MHC class I down-regulation in colon cancer. Given the widespread defects in DNA mismatch repair in colon cancer, mutations at or near the signature domain can potentially modulate antigen processing.
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No. Sentence Comment
152 To substantiate the functional significance of the TAP-1 signature motif, we introduced the following mutations into the signature motif of TAP-1: S644R, G645R, G646S, and G646D (Table 1) by site-directed mutagenesis.
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ABCB1 p.Ser644Arg 15897556:152:147
status: NEW149 To substantiate the functional significance of the TAP-1 signature motif, we introduced the following mutations into the signature motif of TAP-1: S644R, G645R, G646S, and G646D (Table 1) by site-directed mutagenesis.
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ABCB1 p.Ser644Arg 15897556:149:147
status: NEW