The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex.
Major histocompatibility complex (MHC) class I complexes present peptides from both self and foreign intracellular proteins on the surface of most nucleated cells. The assembled heterotrimeric complexes consist of a polymorphic glycosylated heavy chain, non-polymorphic beta(2) microglobulin, and a peptide of typically nine amino acids in length. Assembly of the class I complexes occurs in the endoplasmic reticulum and is assisted by a number of chaperone molecules. A multimolecular unit termed the peptide-loading complex (PLC) is integral to this process. The PLC contains a peptide transporter (transporter associated with antigen processing), a thiooxido-reductase (ERp57), a glycoprotein chaperone (calreticulin), and tapasin, a class I-specific chaperone. We suggest that class I assembly involves a process of optimization where the peptide cargo of the complex is edited by the PLC. Furthermore, this selective peptide loading is biased toward peptides that have a longer off-rate from the assembled complex. We suggest that tapasin is the key chaperone that directs this action of the PLC with secondary contributions from calreticulin and possibly ERp57. We provide a framework model for how this may operate at the molecular level and draw parallels with the proposed mechanism of action of human leukocyte antigen-DM for MHC class II complex optimization.
Elliott
Tim
T
Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK. tje@soton.ac.uk
Williams
Anthony
A
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D017920:Antiporters / Q000276:immunology / Q000378:metabolism; D037282:Calreticulin / Q000276:immunology / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D007535:Isomerases / Q000276:immunology / Q000378:metabolism; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology* / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases
D017920:Antiporters; D037282:Calreticulin; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D018832:Molecular Chaperones; D010455:Peptides; C107762:tapasin; D007535:Isomerases; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human