Mechanistic aspects of tapasin-mediated antigen presentation revealed by structure of a tapasin/MHC-I complex

Abstract T cell immunity to viruses and cancers is crucially dependent on the cell surface display of major histocompatibility complex class I (MHC-I) molecules selectively loaded with high affinity peptides. Peptide loading occurs in the ER within a multimolecular assembly known as the peptide loading complex (PLC). A critical component of the PLC is tapasin, a 45 kDa membrane glycoprotein in whose absence the expression and stability of MHC-I are greatly reduced. To determine the mechanistic basis of tapasin-mediated peptide loading, we determined the crystal structures of human tapasin in complex with HLA-B44:05 as well as tapasin complexed to each of two well-characterized antibodies. The tapasin-stabilized peptide receptive state is characterized by distortions of the peptide binding groove, destabilization of the b 2-microglobulin interaction, and rearrangements of the membrane proximal Ig domains, all of which are reversed on high affinity peptide binding. Additionally, the structural footprints of the anti-tapasin antibodies confirm previous functional assays and together with the tapasin/MHC-I complex and mutagenesis data reveal dynamic aspects of tapasin function. Supported by the Intramural Research Program, NIAID, NIH.