ALTERNATIVE PEPTIDE BINDING MOTIFS OF QA-2 CLASS 1B MOLECULES DEFINE RULES FOR BINDING OF SELF AND NONSELF PEPTIDES

Studies of naturally processed peptides eluted from membrane-bound and soluble isoforms of murine class lb Qa-2 molecules determined several features of these ligands, such as the conserved nonameric length and the preferred usage of specific residues at four to six of nine pepti de positions. The structural information derived from these studies pr oved insufficient to distinguish between two interpretations: 1) that Qa-2 are peptide receptors of higher stringency than ordinary class I molecules, and 2) that Qa-2 molecules, like classical class I Ags, bin d diverse arrays of peptides. We have addressed this issue by a system atic analysis of peptide residues involved in the binding of membrane- bound Qa-2 molecule, MQ9(b). The optimal binding of synthetic peptides in vitro occurs at neutral pH. Two dominant anchors are required for peptide binding to MQ9(b): His at position 7 and a hydrophobic residue , Leu, Ile, or Phe, at position 9. In addition, one or two auxiliary a nchors participate in binding. The identity and the position of the au xiliary anchors differ from peptide to peptide, suggesting that the bi nding motifs defined from pool sequencing are composed of many superim posed alternative motifs present in individual peptides. The number of anchors used by Qa-2 peptides is similar to that found in ligands of classical class I Ags. Consequently, the Qa-2 are predicted to bind la rge repertoires of self and nonself peptides. In support of this inter pretation we demonstrate that MQ9(b) binds strongly 5 of 17 motif-posi tive, pathogen-derived synthetic peptides.