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

Abstract

The human major histocompatibility complex class I antigen HLA-B*2705 binds several sequence-related peptides (pVIPR, RRKWRRWHL; pLPM2, RRRWRRLTV; pGR, RRRWHRWRL). Cross-reactivity of cytotoxic T cells (CTL) against these HLA-B*2705:peptide complexes seemed to depend on a particular peptide conformation that is facilitated by the engagement of a crucial residue within the binding groove (Asp116), associated with a noncanonical bulging-in of the middle portion of the bound peptide. We were interested whether a conformational reorientation of the ligand might contribute to the lack of cross-reactivity of these CTL with a peptide derived from voltage-dependent calcium channel a1 subunit (pCAC, SRRWRRWNR), in which the C-terminal peptide residue pArg9 could engage Asp116. Analyses of the HLA-B*2705:pCAC complex by X-ray crystallography at 1.94 Å resolution demonstrated that the peptide had indeed undergone a drastic reorientation, leading it to adopt a canonical binding mode accompanied by the loss of molecular mimicry between pCAC and sequence-related peptides such as pVIPR, pLMP2, and pGR. This was clearly a consequence of interactions of pArg9 with Asp116 and other F-pocket residues. Furthermore, we observed an unprecedented reorientation of several additional residues of the HLA-B*2705 heavy chain near the N-terminal region of the peptide, including also the presence of double conformations of two glutamate residues, Glu63 and Glu163, on opposing sides of the peptide binding groove. Together with the Arg-Ser exchange at peptide position 1, there are thus multiple structural reasons that may explain the observed failure of pVIPR-directed, HLA-B*2705-restricted CTL to cross-react with HLA-B*2705:pCAC complexes.

Influence of inflammation‐related changes on conformational characteristics of HLA‐B27 subtypes as detected by IR spectroscopy

“…The only difference observed by X-ray crystallography in these structures is a string of water molecules between the a-helix and the major b-sheet that are distinctly located in the wild-type protein and in the variants. As pointed out previously [28], it is conceivable that peptides with a C-terminal basic residue might lead to an altered binding groove flexibility in the B*2705 subtype because of the formation of salt bridges to Asp116 within the molecule's F pocket [17,35,36]. This indicates that the conclusion reached with regard to the enhanced flexibility of the B*2705 HC may not be valid for those complexes that display a peptide with Arg or Lys at the C-terminus (see also [19,25,37] for further discussions).…”

Metal-triggered conformational reorientation of a self-peptide bound to a disease-associated HLA-B*27 subtype

“…SwissProt was accessed on September 15, 2015 to obtain an estimate of the number of human protein-derived nonamer peptides that could principally be presented by B*27:05 and allow metal-induced conformational reorientations. The peptides had to meet the following criteria: no Pro at p1 (Pro is not accepted at this position), pArg-2 (a nearly obligatory anchor for HLA-B*27 molecules (25), no Asp or Glu at p9 (these would not bind with high affinity to B*27:05), and also no Arg or Lys at this position (contact with Asp-116 would preclude the interaction between pArg-5 and Asp-116) (66). As a potential contact site for a metal ion, pHis-8 should also be present as well as a basic residue at p5 to allow binding to HC residue Asp-116 in the NC conformation.…”