Association of beta2-microglobulin with the alpha3 domain of H-2Db heavy chain

MHC class I molecules are heterotrimeric complexes composed of heavy chain, beta2-microglobulin (beta2m) and short peptide. This trimeric complex is generated in the endoplasmic reticulum (ER), where a peptide loading complex (PLC) facilitates transport from the cytosol and binding of the peptide to the preassembled ER resident heavy chain/beta2m dimers. Association of mouse MHC class I heavy chain with beta2m is characterized by allelic differences in the number and/or positions of amino acid interactions. It is unclear, however, whether all alleles follow common binding patterns with minimal contributions by allele-specific contacts, or whether essential contacts with beta2m are different for each allele. While searching for the PLC binding site in the alpha3 domain of the mouse MHC class I molecule H-2Db, we unexpectedly discovered a site critical for binding mouse, but not human, beta2m. Interestingly, amino acids in the corresponding region of another MHC class I heavy chain allele do not make contacts with the mouse beta2m. Thus, there are allelic differences in the modes of binding of beta2m to the heavy chain of MHC class I.