Presentation of Cytosolically Stable Peptides by HLA-B27 Is Not Dependent on the Canonic Interactions of N-Terminal Basic Residues in the A Pocket

Abstract

HLA-B27 binds peptides with R at position 2. Additionally, a substantial fraction of the HLA-B27-bound peptide repertoire has basic residues at position 1. It is unclear whether this is determined by structural complementarity with the A pocket of the peptide-binding site, by the increased availability of peptides with dibasic N-terminal sequences resulting from their cytosolic stability, or both. To distinguish between these possibilities two B*2705 mutants were generated in which one or two A pocket surface residues stabilizing the peptidic R1 side chain were changed: E163T and E163T-W167S. Both mutants bound a large fraction of the constitutive peptide repertoire of B*2705. Moreover, 90 B*2705 ligands of known sequence were examined for their endogenous presentation by the mutants. The E163T mutation alone had a limited effect on binding of peptides with R1 or K1 and on the relative frequencies of N-terminal residues. However, it decreased the overall stability of the molecule. The E163T-W167S mutant also bound many of the B*2705 ligands with N-terminal basic residues, but its preference for G1 was significantly decreased. The results indicate that the capacity of HLA-B27 to bind peptides with N-terminal basic residues is largely independent of the canonic interactions that stabilize at least the R1 side chain. Thus, the prevalence of HLA-B27 ligands with dibasic N-terminal sequences may be significantly influenced by the increased availability of these peptides resulting from their cytosolic stability. This confers to HLA-B27 a unique capacity to present Ags generated in low amounts, but resistant to intracellular degradation.

Dynamical Characterization of Two Differentially Disease Associated MHC Class I Proteins in Complex with Viral and Self-Peptides

“…12,14,32,52,53 Nevertheless, the comparison of the two minimally distinct B * 27:05 and B * 27:09 subtypes has already provided important insights that cannot be obtained by studying only a single allele such as HLA-A * 02:01. In particular, it has been possible to shed light on the structural basis for the observation that also a hidden polymorphic residue can decisively contribute to the differential selection of T-cell repertoires.…”

Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes

“…To this regard, it has been shown that mutations of Glu163 alone or both Glu163 and Trp167 had a limited effect on the B*2705 molecules for usage of peptides with basic P1 residues, thus indicating that the increased cytosolic stability is responsible for such a preferential binding [54]. However, B*2705 mutants substituted at Arg62 residue have never been generated and assessed for their peptide binding repertoire.…”

Loss of recognition by cross‐reactive T cells and its relation to a C‐terminus‐induced conformational reorientation of an HLA‐B*2705‐bound peptide

“…However, the relatively frequent occurrence of the N‐terminal pArg1‐pArg2 sequence in peptides bound by HLA‐B27 may not exclusively be a consequence of the Arg62‐pArg1‐Trp167 stacking interaction, as peptides with the pArg1‐pArg2 motif appear to have an increased cytosolic stability 35. In support of this contention, López de Castro and co‐workers concluded that the preferential ability of HLA‐B27 molecules to bind peptides with the dibasic N‐terminal motif is probably not connected to the presence of Glu163 and Trp167, since mutations of these residues do not seem to affect the frequency with which pArg1‐pArg2‐containing peptides are bound 36…”