ABCMdb

ABCB2 p.Gly645Arg

Predicted by SNAP2:	A: N (66%), C: D (63%), D: D (75%), E: D (75%), F: D (80%), H: D (66%), I: D (75%), K: D (85%), L: D (75%), M: D (66%), N: N (53%), P: D (80%), Q: D (59%), R: D (75%), S: N (87%), T: D (66%), V: D (75%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D,

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Publications
[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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3 In addition, we found that mutations S644R, G645R, G646S, and G646D interfered withTAP-1activity.TAP-1G646D, 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. Login to comment
67 Nucleotide changes and amino acid substitutions generated by site-directed mutagenesis Signature motif sequence Nucleotide change Amino acid change LSGGQ TCA >CGA S644R LSGGQ GGG >CGG G645R LSGGQ GGT >GAT G646D LSGGQ GGT >AGT G646S Golden, CO), which were diluted in 200 AL of dilution buffer (PBS containing 3% bovine serum and 0.2% Triton X-100) were added. Login to comment
149 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. Login to comment
186 A, SK-MEL-19 cell clones stably transfected with theTAP-1mutants, G644R, G645R, G646S, and G646Das indicated were examined for their surface MHC class Iby flow cytometry after being stained with a phycoerythrin-conjugated anti-human HLA-A, B, and C antibody (boldline) or isotype control (phycoerythrin-conjugated mouse IgG1 , dotted lines). Login to comment