A role for the P1 anchor residue in the thermal stability of MHC class II molecule I-Ab

The thermal stability of the murine MHC class II molecule, I-A(b), in complex with invariant chain-derived peptide (CLIP) and an antigenic peptide derived from the alpha subunit of the I-E molecule (Ealpha) at mildly acidic and neutral pH were analyzed using circular dichroism (CD). The stability of I-A(b)-CLIP was increased by a single amino acid substitution in the P1 anchor residue, from Met of CLIP to Phe of Ealpha, similar, in this respect, to I-A(b) -Ealpha. This indicates that hydrophobic interaction in the P1 pocket is critical and plays a primary role in the stability of the complex. The structural models of I-A(b)-peptides based on the crystal structure of I-A(d) might explain the increased stability and the preference for hydrophobic residues in this site. Taken together with what is known of the resident stability at a mildly acidic pH, the difference in stability would closely correlate with the ability of MHC class II to exchange peptides from CLIP to antigenic peptides in the endosome. (C) 2002 Elsevier Science B.V. All rights reserved.