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  • br MHCI peptide editing N terminal extensions

    2024-04-11


    MHCI peptide editing, N-terminal extensions and the peptide loading complex Conventionally, peptide-MHCI binding is thought to require both amino- and carboxyl-termini for stable interaction (Madden, 1995; Bouvier and Wiley, 1994). Peptides with longer than optimal length (10–13 residues) have been observed to bind, but in a bulged conformation with buried termini and exposed central regions (Tynan et al., 2005). This might be thought to preclude on-MHC processing by ERAP, which requires a free amino terminus. Recently two groups have reported peptide-MHCI structures with protruding N-termini, for an HIV gag-derived epitope binding/bound to HLA-B57 (Pymm et al., 2017) or HLA-B58 (Li et al., 2017). These add to an earlier report of a LCMV gp33-derived epitope binding to H2-Kb with an exposed N-terminal residue (Achour et al., 2002). In each of these cases the peptide is bound throughout the full length of the peptide binding site, occupying with a small Ser or Ala side chain the “A pocket” that usually accommodates the amino terminus, making a sharp kink Ro 48-8071 stabilized by several hydrogen bonds that orient one or two amino terminal residues outside the groove. Although these structures reveal an exposed amino-terminal residue, trimming by ERAP1 to generate a conventional 9mer-residue peptide would appear to require breaking many peptide-MHC interactions so that the active site could access the scissile bond. Even for the “wide-open” ERAP1 conformation, which is more “open” than currently observed by X-ray crystallography or SAXS, ERAP1 trimming has been estimated to require at least four residues protruding beyond the last MHC interaction sites (Stratikos and Stern, 2013; Papakyriakou and Stratikos, 2017). Thus these N-extended conformations are not likely to represent ERAP1 substrates without considerable additional structural rearrangement or stabilization of the MHC with partially-occupied peptide. It is possible that cellular antigen presentation machinery can stabilize a complex between MHC and partially-bound peptide in a conformation that is suitable for on-MHC trimming. Nascent MHCI Ro 48-8071 without peptides are kept in a receptive state, through the formation of a complex (peptide loading complex, PLC) with TAP and other ER chaperone proteins, including tapasin, calnexin, calreticulin, ERp57 and protein disulfide isomerase, PDI (Hulpke and Tampe, 2013; Cresswell et al., 1999). In this complex, tapasin interacts directly with MHCI molecules and is required for optimal peptide loading (Williams et al., 2002) via a peptide editing process (Thomas and Tampe, 2017), calnexin and calreticulin stabilize the heavy chain before β2-microglobulin association, and ERp57 is a thioreductase that supports the formation of a disulfide bridge that connects the walls of the MHCI peptide-binding groove with its base (Cresswell et al., 1999). A recently determined structure of the PLC by cryo-EM has shed light on the structural composition of the complex but did not contain ERAP1, although some room for additional interactions is available (Blees et al., 2017). The exact manner in which peptide enters the peptide loading complex is not clear, and it is possible that a complex of stabilized MHC with partially bound peptide is suitable for ERAP processing. ERAP1 has not been shown to directly interact with this complex, but thiol-dependent interactions similar to those observed for ERp44 could be envisioned that might promote processing of transient states.
    Role of ERAP1 in antigenic peptide destruction Whereas the two pathways described above present distinct strategies for generating MHCI peptide ligands, they also may affect the ability of ERAP1 to overtrim peptides to lengths too short for forming stable complexes with MHCI. Several studies have suggested an important role of ERAP1 in destroying peptides by overtrimming, effectively eradicating a pool of peptides from the antigenic peptide repertoire (York et al., 2002; Hammer et al., 2007; Nagarajan et al., 2016; Barnea et al., 2017; Seregin et al., 2013). MHCI have also been demonstrated to be able to protect good peptide ligands from ERAP1 degradation (Infantes et al., 2010; Kanaseki et al., 2006). In Pathway #1, peptide destruction can occur in solution, determined by the affinity of the peptide for ERAP1. Conversely in Pathway #2, destruction can occur on-MHC, determined by a combination of peptide affinity for ERAP1 and MHCI. A combination of both processes however is also possible, with weakly-binding peptides dissociating off the MHCI to be trimmed by ERAP1 in solution. Currently however, the relative importance of destruction versus generation for shaping the immunopeptidome is not clear.