Determinants of the peptide induced conformational change in the human class II major histocompatibility complex protein HLA-DR1

The human class II major histocompatibility complex protein HLA-DR1 has bee n shown previously to undergo a distinct conformational change from an open to a compact form upon binding peptide, To investigate the role of peptide in triggering the conformational change, the minimal requirements for indu cing the compact conformation were determined. Peptides as short as two and four residues, which occupy only a small fraction of the peptide-binding c left, were able to induce the conformational change. A mutant HLA-DR1 prote in with a substitution in the beta subunit designed to fill the P1 pocket f rom within the protein (Gly(86) to Tyr) adopted to a large extent the compa ct, peptide-bound conformation. Interactions important in stabilizing the c ompact conformation are shown to be distinct from those responsible for hig h affinity binding or for stabilization of the complex against thermal dena turation. The results suggest that occupancy of the P1 pocket is responsibl e for partial conversion to the compact form but that both side chain and m ain chain interactions contribute to the full conformational change. The im plications of the conformational change to intracellular antigen loading an d presentation are discussed.