Insights into antigen processing and presentation from crystal structures of ERAP1 and HLA-DR1(F54C

MHC proteins bind short peptides in various intracellular compartments and carry them out the to cell surface for presentation to T lymphocytes, as part of the mechanism by which the immune system surveys the body for infection.  Intracellular processing pathways have evolved to shunt peptides derived from protein turnover and housekeeping proteolysis into specialized pathways that load the peptides onto MHC proteins for trafficking to the cell surface.  One component of the pathway is ERAP1, an ER-resident aminopeptidase that trims peptides transported into ER so that they are the correct length for loading onto class I MHC proteins.  ERAP1's enzymatic activity is unusual among aminopeptidases in that is highly dependent on the length of its peptide substrate, with efficient processing restricted to peptides 7-8 residues or longer.  Structural analysis shows that ERAP1 has a large compartment extending from the active site, with a large-scale conformational change regulating access to the compartment.  Kinetics studies reveal an interesting regulatory mechanism controlled by occupancy of subsites within the overall binding compartment.  Together these provide a possible model for the length-dependent cleavage activity.  Another component is HLA-DM, an endosome-resident peptide exchange catalyst that helps to load peptides onto class II MHC proteins.  HLA-DM functions by inducing conformational changes in its class II MHC substrate, but its mechanism has been obscure. The crystal structure of a class II MHC mutant protein with extraordinary susceptibility to HLA-DM action reveals conformational changes around the P1 substrate binding pocket, and hydrogen-deuterium exchange mass spectrometry reveals altered MHC-peptide hydrogen bonding pattern. Together these provide a possible mechanism for HLA-DM's enigmatic conformational catalysis mechanism.