Conformational Dimorphism of Self-peptides and Molecular Mimicry in a Disease-associated HLA-B27 Subtype

Rückert, Christine; Fiorillo, Maria Teresa; Loll, Bernhard; Moretti, Roberto; Biesiadka, Jacek; Saenger, Wolfram; Ziegler, Andreas; Sorrentino, Rosa; Uchańska-Ziegler, Barbara

doi:10.1074/jbc.m508528200

Cited by 51 publications

(58 citation statements)

References 60 publications

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“…However, it is currently unclear whether vasoactive intestinal peptide type 1 receptor can be modified by citrullination such that pVIPR-U5 could be cleaved from it or whether the proteolysis-derived peptide might itself be subject to citrullination. In this context, it is important to point out that it is principally possible that pVIPR is just an innocent bystander in AS development as unidentified peptides that exhibit structural, but not necessarily sequence similarity with pVIPR might be the pathogenetically relevant targets that are recognized by cross-reactive CTL (20,21). Therefore, the model character of our study has to be emphasized.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it would belong into the realm of speculation to ascribe a specific role to citrullinated peptides in the pathogenesis of autoimmune disorders; for example, in the context of molecular mimicry between foreign and self-peptides in AS (14,20,21) or other diseases. Whether conformational reorientations of MHC ligands, comparable with those described here, can affect also citrullinated pathogen-derived peptides such as pLMP2 (RRRWRRLTV; from the latent membrane protein 2 of Epstein-Barr virus) remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

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Citrullination-dependent Differential Presentation of a Self-peptide by HLA-B27 Subtypes

Beltrami

Rossmann

Fiorillo

et al. 2008

Journal of Biological Chemistry

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Inflammatory processes are accompanied by the posttranslational modification of certain arginine residues within proteins to yield citrulline, although it is largely unknown how this modification influences antigen presentation. We employed crystallographic and functional studies to investigate whether the exchange of arginine to citrulline affects the display of a peptide by two human major histocompatibility antigen class I subtypes, HLA-B*2705 and HLA-B*2709. Both differ only in residue 116 within the peptide binding groove despite their differential association with ankylosing spondylitis, an inflammatory rheumatic disorder. The crystal structures described here show that a modified self-peptide, pVIPR-U5 (RRKWURWHL; U ‫؍‬ citrulline), is presented by the two HLA-B27 molecules in distinct conformations. These binding modes differ not only drastically from each other but also from the conformations exhibited by the non-citrullinated peptide in a given subtype. The differential reactivity of HLA-B27-restricted cytotoxic T cells with modified or unmodified pVIPR supports the structural findings and shows that the presentation of citrullinated peptides has the potential to influence immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Citrullination-dependent Differential Presentation of a Self-peptide by HLA-B27 Subtypes

Beltrami

Rossmann

Fiorillo

et al. 2008

Journal of Biological Chemistry

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“…In case of pGR, which exhibits high sequence similarity with pLMP2 and pVIPR, the peptide is bound to B*2705 in a double nonstandard conformation in which pHis-5 is not directly connected to Asp-116, in contrast to pArg-5 of the pVIPR and pLMP2 peptides (15). Both peptides (TIS, pGR) exhibit transition temperatures for thermal peptide unbinding in the narrow range between 57 and 60°C (330 and 333 K), regardless of their binding to B*2705 or B*2709.…”

Section: Resultsmentioning

confidence: 99%

“…Protein Preparation-Complexes of the subtypes B*2705 and B*2709 with the peptides m9, pVIPR, TIS, pLMP2, gag, pGR, and the artificial peptide mutants pVIPR-H8T and pLMP2-T8H were prepared as described previously (10,11,(13)(14)(15)(16)(17)(18)26). The synthetic peptides as well as their fluorescent derivatives labeled with Lucifer Yellow (LY, Molecular Probes) in position C-6 and C-8, respectively, were purchased from Alta Bioscience (Birmingham, UK), Biosynthan (Berlin, Germany), or synthesized in-house.…”

Section: Methodsmentioning

confidence: 99%

“…Several theories seeking to explain the disease association have been published over the years, most of them regarding the molecule and its peptide binding properties as a key to the pathogenic role of HLA-B27 (7). This holds true for the hypotheses of molecular mimicry between foreign and selfpeptides presented by HLA-B27 (14,15,17), but also for the involvement of misfolded or partially unfolded molecules (19), heavy chain homodimers (20), or liberated ␤ 2 m (21). Despite these efforts, the molecular basis of the strong linkage of HLA-B27 with spondyloarthropathies still remains elusive.…”

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confidence: 99%

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Molecular Determinants of Major Histocompatibility Complex Class I Complex Stability

Narzi

Winkler

Saidowsky

et al. 2008

Journal of Biological Chemistry

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HLA–B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility

Fabian¹,

Huser²,

Loll³

et al. 2010

Arthritis & Rheumatism

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Objective. Although the products of the HLA subtypes B*2705 and B*2709 differ only in residue 116 (Asp versus His) within their peptide-binding grooves, they are differentially associated with inflammatory rheumatic diseases such as ankylosing spondylitis (AS): B*2705 occurs in AS patients, whereas B*2709 is only rarely encountered. The reasons for this distinct association are still unclear but could include subtypespecific conformational and dynamic properties of these antigens. The present study was undertaken to investigate structural and dynamic differences between B*2705 and B*2709 and their possible relationship to subtypespecific disease association.Methods. The membrane-distal segments of the B*2705 and B*2709 heavy chains were expressed in vitro and reconstituted together with ␤ 2 -microglobulin and a peptide. HLA-B27 complexes loaded with 2 self peptides (TIS [RRLPIFSRL] and pVIPR [RRKWRRWHL]) and a sequence-related viral peptide (pLMP2 [RRRWRRLTV]) were studied by isotope-edited infrared spectroscopy to detect differences in their structure and flexibility at physiologic temperature.Results. Our analyses revealed the existence of subtype-specific conformational differences between the 2 HLA-B27 heavy chains at physiologic temperature, which are undetectable using x-ray crystallography. Irrespective of the bound peptide, the heavy chain of the B*2705 complex exhibited higher conformational flexibility than the B*2709 heavy chain.Conclusion. The present study demonstrates the existence of previously undetected systematic conformational and dynamic differences between the heavy chains of the 2 HLA-B27 subtypes. Since effector cell recognition of cells expressing HLA antigens is dependent on the dynamic properties of the interacting cell surface molecules, this HLA-B27 subtype-specific heavy chain flexibility could have a role in the distinct association of HLA-B27 subtypes with spondylarthritides.

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Conformational Dimorphism of Self-peptides and Molecular Mimicry in a Disease-associated HLA-B27 Subtype

Cited by 51 publications

References 60 publications

Citrullination-dependent Differential Presentation of a Self-peptide by HLA-B27 Subtypes

Citrullination-dependent Differential Presentation of a Self-peptide by HLA-B27 Subtypes

Molecular Determinants of Major Histocompatibility Complex Class I Complex Stability

HLA–B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility

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