ABCB1 p.Arg659Gln
| Predicted by SNAP2: | A: N (66%), C: N (53%), D: D (59%), E: N (57%), F: D (53%), G: D (53%), H: N (66%), I: N (57%), K: N (82%), L: N (57%), M: N (53%), N: N (66%), P: D (53%), Q: N (82%), S: N (82%), T: N (72%), V: N (57%), W: D (66%), Y: D (53%), |
| 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, S: 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
220 In fact, in a previous study (19), no cell surface HLA was detectable in a small cell lung cancer cell line due to selective expression of another TAP-1 variant, R659Q, which was later shown to have as much as 50% of wild-type transporter activity (34).
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ABCB1 p.Arg659Gln 15897556:220:162
status: NEW217 In fact, in a previous study (19), no cell surface HLA was detectable in a small cell lung cancer cell line due to selective expression of another TAP-1 variant, R659Q, which was later shown to have as much as 50% of wild-type transporter activity (34).
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ABCB1 p.Arg659Gln 15897556:217:162
status: NEW[hide] Function of the transport complex TAP in cellular ... Biochim Biophys Acta. 1999 Dec 6;1461(2):405-19. Abele R, Tampe R
Function of the transport complex TAP in cellular immune recognition.
Biochim Biophys Acta. 1999 Dec 6;1461(2):405-19., [PMID:10581370]
Abstract [show]
The transporter associated with antigen processing (TAP) is essential for peptide loading onto major histocompatibility complex (MHC) class I molecules by translocating peptides into the endoplasmic reticulum. The MHC-encoded ABC transporter works in concert with the proteasome and MHC class I molecules for the antigen presentation on the cell surface for T cell recognition. TAP forms a heterodimer where each subunit consists of a hydrophilic nucleotide binding domain and a hydrophobic transmembrane domain. The transport mechanism is a multistep process composed of an ATP-independent peptide association step which induces a structural reorganization of the transport complex that may trigger the ATP-driven transport of the peptide into the endoplasmic reticulum lumen. By using combinatorial peptide libraries, the substrate selectivity and the recognition principle of TAP have been elucidated. TAP maximizes the degree of substrate diversity in combination with high substrate affinity. This ABC transporter is also unique as it is closely associated with chaperone-like proteins involved in bonding of the substrate onto MHC molecules. Most interestingly, virus-infected and malignant cells have developed strategies to escape immune surveillance by affecting TAP expression or function.
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No. Sentence Comment
386 In addition, both NBDs are essential for TAP function because mutation of one NBD (R659Q of hTAP1) leads to a loss of transport function [90].
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ABCB1 p.Arg659Gln 10581370:386:83
status: NEW501 Another interesting example of a tumor escape mechanism was found in small lung cancer where a TAP1 (R659Q) mutant was identi'ed [90].
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ABCB1 p.Arg659Gln 10581370:501:101
status: NEW