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The peptide-binding motif for the human transporter associated with antigen processing
P M van Endert1, D Riganelli, G Greco
1Institut National de la Santé et de la Recherche Medicale Unité 25, Paris, France.
The Journal of Experimental Medicine
|December 1, 1995
Summary
The transporters associated with antigen processing (TAP) select antigenic peptides for presentation by human leukocyte antigen class I molecules. TAP favors specific amino acid residues, influencing peptide binding and potentially impacting immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Peptide transport into the endoplasmic reticulum by transporters associated with antigen processing (TAP) is crucial for human leukocyte antigen (HLA) class I presentation.
- This translocation step was previously considered permissive for all peptides that could bind to HLA class I molecules.
Purpose of the Study:
- To investigate the peptide selection mechanism of the human TAP transporter.
- To determine the binding motif and preferences of TAP for peptide translocation.
- To assess the implications of TAP's selectivity for HLA class I peptide presentation.
Main Methods:
- Analysis of peptide binding affinities to the human TAP transporter.
- Characterization of the effects of specific amino acid residues at different peptide positions (NH2-terminal and COOH-terminal) on TAP affinity.
- Comparison of TAP preferences with known HLA class I binding motifs.
Main Results:
- The human TAP transporter exhibits specific peptide selection based on a binding motif.
- TAP strongly favors hydrophobic residues at position 3 (P3) and hydrophobic or charged residues at position 2 (P2).
- Aromatic or acidic residues at position 1 (P1), and Proline at P1 or P2, have detrimental effects on TAP binding.
- Naturally presented peptides show higher average affinity for TAP, suggesting selection.
- TAP preferences align with most HLA class I alleles but pose challenges for certain groups, like the B7-like alleles.
Conclusions:
- TAP actively selects peptides, it is not a permissive transporter.
- TAP's binding motif influences the repertoire of peptides presented by HLA class I molecules.
- Peptide transport may occur as extended precursors for peptides with low TAP affinity or for specific HLA alleles.