Structural relatedness of distinct determinants recognized by monoclonal antibody TP25.99 on β2-microglobulin-associated and β2-microglobulin-free HLA class I heavy chains

The association of HLA class I heavy chains with beta (2)-microglobulin (beta (2)m) changes their antigenic profile. As a result, Abs react with either beta (2)m-free or beta (2)m-associated HLA class I heavy chains. An exception to this rule is the mAb TP25,99, which reacts with both beta (2)m-associated and beta (2)m-free HLA class I heavy chains. The reactivity with beta (2)m-associated HLA class I heavy chains is mediated by a conformational determinant expressed on all HLA-A, -B, and -C Ags, This determinant has been mapped to amino acid residues 194-198 in the alpha3 domain, The reactivity with beta (2)m-free HLA class I heavy chains is mediated by a linear determinant expressed on all HLA-B Ags except the HLA-B73 allospecificity and on <50% of HLA-A allospecificities, The latter determinant has been mapped to amino acid residues 239-242, 245, and 246 in the <alpha>3 domain. The conformational and the linear determinants share several structural features, but have no homology in their amino acid sequence. mAb TP25,99 represents the first example of a mAb recognizing two distinct and spatially distant determinants on a protein. The structural homology of a linear and a conformational determinant on an antigenic entity provides a molecular mechanism for the sharing of specificity by B and TCRs.