Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide

Abstract

The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

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

“…1). This contrasts with the recent structure of HLA-B*2705 complexed with a self peptide which showed a dual conformation of the peptide [21]. Superimpositions based on Ca atoms reveal that the side chain of the P2 arginine occupies almost identical positions in all HLA-B*2705 structures solved to date.…”

“…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.…”

“…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

“…These interactions are little affected by changes at residue 116 [18], so that peptides with aliphatic P residues are largely shared between HLA-B27 subtypes differentially associated with AS [19,20].…”

“…Two examples have been reported. One peptide showed a dual, canonical and non-canonical, conformation [18]. The other one adopted only the non-canonical binding mode [23].…”