THE PEPTIDE-BINDING MOTIF FOR THE HUMAN TRANSPORTER ASSOCIATED WITH ANTIGEN-PROCESSING

Presentation of antigenic peptides by human leukocyte antigen class I molecules is dependent on peptide transport into the endoplasmic retic ulum by the transporters associated with antigen processing (TAP) (Ger main, R. N. 1994. Cell. 76:287-299). This translocation step is curren tly regarded as permissive for all peptides with COOH-terminal residue s 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. Na ture (Lend.). 367:648-651). In this report, we show that the human tra nsporter selects peptides according to a binding motif based on the st rong effects on peptide affinity of the three NH2-terminal positions a nd the COOH-terminal residues. TAP favors strongly hydrophobic residue s in position 3 (P3) and hydrophobic or charged residues in P2, wherea s 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 t hree NH2-terminal positions correspond to those of the vast majority o f human leukocyte antigen class I alleles, but they represent an obsta cle for peptide supply to some alleles, e.g., the B7-like group. We pr opose that peptides binding to these alleles, and in general, peptides with TAP affinities below a certain threshold, may be transported as extended precursors.