A Conformational Change in the Human Major Histocompatibility Complex Protein HLA-DR1 Induced by Peptide Binding†

ABSTRACT: To investigate a conformational change accompanying peptide binding to class II MHC proteins, we probed the structure of a soluble version of the human class II MHC protein HLA-DR1 in empty and peptide-loaded forms. Peptide binding induced a large decrease in the effective radius of the protein as determined by gel filtration, dynamic light scattering, and analytical ultracentrifugation. It caused a substantial increase in the cooperativity of thermal denaturation and induced alterations in MHC polypeptide backbone structure as determined by circular dichroism. These changes suggest a condensation of the protein around the bound peptide. An antibody specific for â58-69 preferentially bound the empty protein, indicating that the peptide-induced conformational change involves the â-subunit helical region. The conformational change may have important implications for the mechanisms of intracellular antigen presentation pathways. Major histocompatibility complex (MHC)1 proteins are heterodimeric cell-surface proteins that serve as restricting elements for the cell-mediated immune system. Class II MHC proteins bind peptides produced by endosomal proteolysis and present them at the cell surface for recognition by CD4