Thermodynamic and Structural Analysis of Peptide- and Allele-dependent Properties of Two HLA-B27 Subtypes Exhibiting Differential Disease Association

Abstract

Selected HLA-B27 subtypes are associated with spondyloarthropathies, but the underlying mechanism is not understood. To explain this association in molecular terms, a comparison of peptide-dependent dynamic and structural properties of the differentially disease-associated subtypes HLA-B*2705 and HLA-B*2709 was carried out. These molecules differ only by a single amino acid at the floor of the peptide binding groove. The thermostabilities of a series of HLA-B27 molecules complexed with nonameric and decameric peptides were determined and revealed substantial differences depending on the subtype as well as the residues at the termini of the peptides. In addition we present the crystal structure of the B*2709 subtype complexed with a decameric peptide. This structure provides an explanation for the preference of HLA-B27 for a peptide with an N-terminal arginine as secondary anchor and the lack of preference for tyrosine as peptide C terminus in B*2709. The data show that differences in thermodynamic properties between peptide-complexed HLA-B27 subtypes are correlated with a variety of structural properties.

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

“…Our data show that HLA-B*2705 binds three immunodominant viral epitopes in a canonical extended conformation, similar to the self peptides studied previously [10,11,21,22,29]. By doubling the number of HLA-B*2705-peptide structures (from three to six), we show how HLA-B*2705 can bind peptides in subtly different ways.…”

“…1h) in a relatively focused loop. This contrasts with structures of other decameric peptides, such as the HLA-B*2709-s10 complex, where the peptide forms a broad bulge extending out from the groove between the P4-P10 peptide residues [22], and in the HLA-A2-gp120 complex, where the length of the peptide is contained in a zig-zag conformation within the peptide-binding groove [23]. The large 13-mer peptide in the rat RT1-Aa-MTF-E complex showed a striking bulge protruding from the central region of the peptide-binding groove, and multiple conformations of the bulge were evident, in contrast with the single conformation observed with the HLA-B*2705-HIV peptide here [24].…”

“…A different coordination network of the P2R by the E63/ E45 pair has been described previously -from crystals grown at pH 8.5 or 9.0 -that may have altered the protonation state of these acidic side chains [29]. Since the E45/E63/PR2 coordination network found in an additional B*2709-decameric-self-peptide structure solved at pH 8.0 [22] is identical to the three P2R coordination networks in this study (solved at pH 6.5), it is likely that the coordination of P2R found here represents the network found at physiological pH.…”

“…Elution studies of peptide repertoires have shown that basic amino acids or tyrosine are infrequently observed at the PC position of HLA-B*2709, whereas positively charged amino acids are common at the C termini of HLA-B*2705 epitopes [33]. Furthermore, recent crystallographic studies have shown both different F-pocket binding for B*2709, and also the ability of HLA-B*2705 to bind a self peptide in two conformations, with a peptide-P5-side-chain interaction with D116 in one [21,22,29].…”

HLA‐B27: portraying immunodominant viral epitopes

“…R2 adopts a universal binding mode, in which the guanidinium group is tightly hydrogenbonded to multiple B-pocket residues. Deviations from this pattern, observed at high pH, are probably artifactual [16]. This close complementarity explains why very few B*2705 ligands with P2 residues other than R are known [14].…”