A rare transporter associated with antigen processing polymorphism overpresented in HLAlow colon cancer reveals the functional significance of the signature domain in antigen processing

Tianyu Yang, Philip E. Lapinski, Haotian Zhao, Qunmin Zhou, Huiming Zhang, Malini Raghavan, Yang Liu, Pan Zheng

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3614-3623
Number of pages10
JournalClinical Cancer Research
Volume11
Issue number10
DOIs
StatePublished - May 15 2005

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Antigen Presentation
Colonic Neoplasms
Endoplasmic Reticulum
Peptides
ATP-Binding Cassette Transporters
Nucleotides
Amino Acid Motifs
Mutation
DNA Mismatch Repair
Membranes
Exons
Membrane Proteins
Down-Regulation
Adenosine Triphosphate
Alleles

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A rare transporter associated with antigen processing polymorphism overpresented in HLAlow colon cancer reveals the functional significance of the signature domain in antigen processing. / Yang, Tianyu; Lapinski, Philip E.; Zhao, Haotian; Zhou, Qunmin; Zhang, Huiming; Raghavan, Malini; Liu, Yang; Zheng, Pan.

In: Clinical Cancer Research, Vol. 11, No. 10, 15.05.2005, p. 3614-3623.

Research output: Contribution to journalArticle

Yang, Tianyu ; Lapinski, Philip E. ; Zhao, Haotian ; Zhou, Qunmin ; Zhang, Huiming ; Raghavan, Malini ; Liu, Yang ; Zheng, Pan. / A rare transporter associated with antigen processing polymorphism overpresented in HLAlow colon cancer reveals the functional significance of the signature domain in antigen processing. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 10. pp. 3614-3623.
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AB - 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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