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A Rare Transporter Associated with Antigen Processing Polymorphism Overpresented in HLA^low Colon Cancer Reveals the Functional Significance of the Signature Domain in Antigen Processing

Authors' Affiliations: ¹ Division of Cancer Immunology, Department of Pathology and Comprehensive Cancer Center, ² Graduate Program in Molecular, Cellular, and Developmental Biology, The Ohio State University, ³ OncoImmune, Ltd., Columbus, Ohio, and ⁴ Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan

Requests for reprints: Pan Zheng, Division of Cancer Immunology, Department of Pathology and Comprehensive Cancer Center, The Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Phone: 614-292-2003; Fax: 614-688-8152; E-mail: zheng-1{at}medctr.osu.edu.

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.

Key Words: TAP-1 Polymorphism • antigen presentation • structure and function • signature motif • human leukocyte antigens • Polymorphisms related to inflammation, immune response, and oxidative damage in cancer risk • immunomodulation

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