The peptide-binding motif for the human transporter associated with antigen processing

doi:10.1084/jem.182.6.1883

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The peptide-binding motif for the human transporter associated with antigen processing

PM van Endert, D Riganelli, G Greco, K Fleischhauer, J Sidney, A Sette and JF Bach
Institut National de la Sante et de la Recherche Medicale Unite 25, Paris, France.

Presentation of antigenic peptides by human leukocyte antigen class I molecules is dependent on peptide transport into the endoplasmic reticulum by the transporters associated with antigen processing (TAP) (Germain, R. N. 1994. Cell. 76:287-299). This translocation step is currently regarded as permissive for all peptides with COOH-terminal residues capable of binding to HLA class I molecules (Momburg, F., J. Roelse, J. C. Howard, G. W. Butcher, G.J. Hammerling, and J.J. Neefjes. 1994. Nature (Lond.). 367:648-651). In this report, we show that the human transporter selects peptides according to a binding motif based on the strong effects on peptide affinity of the three NH2-terminal positions and the COOH-terminal residues. TAP favors strongly hydrophobic residues in position 3 (P3) and hydrophobic or charged residues in P2, whereas aromatic or acidic residues in P1, as well as Pro in P1 and P2, have strong deleterious effects. Selection of naturally presented peptides by the transporter is suggested by their higher average affinity for TAP, as compared to nonselected peptides. The TAP preferences in the three NH2-terminal positions correspond to those of the vast majority of human leukocyte antigen class I alleles, but they represent an obstacle for peptide supply to some alleles, e.g., the B7-like group. We propose that peptides binding to these alleles, and in general, peptides with TAP affinities below a certain threshold, may be transported as extended precursors.
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