Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer.
Tapasin is a glycoprotein critical for loading major histocompatibility complex (MHC) class I molecules with high-affinity peptides. It functions within the multimeric peptide-loading complex (PLC) as a disulfide-linked, stable heterodimer with the thiol oxidoreductase ERp57, and this covalent interaction is required to support optimal PLC activity. Here, we present the 2.6 A resolution structure of the tapasin-ERp57 core of the PLC. The structure revealed that tapasin interacts with both ERp57 catalytic domains, accounting for the stability of the heterodimer, and provided an example of a protein disulfide isomerase family member interacting with substrate. Mutational analysis identified a conserved surface on tapasin that interacted with MHC class I molecules and was critical for peptide loading and editing functions of the tapasin-ERp57 heterodimer. By combining the tapasin-ERp57 structure with those of other defined PLC components, we present a molecular model that illuminates the processes involved in MHC class I peptide loading.
Dong
Gang
G
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
Wearsch
Pamela A
PA
Peaper
David R
DR
Cresswell
Peter
P
Reinisch
Karin M
KM
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D019281:Dimerization; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000276:immunology*; D011490:Protein Disulfide Reductase (Glutathione) / Q000737:chemistry* / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary
D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D010455:Peptides; C107762:tapasin; D011490:Protein Disulfide Reductase (Glutathione); D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human