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

Beltrami, A.; Rossmann, Maxim; Fiorillo, Maria Teresa; Paladini, Fabiana; Sorrentino, Rosa; Saenger, Wolfram; Kumar, Pravin; Ziegler, Andreas; Uchańska-Ziegler, Barbara

doi:10.1074/jbc.m802818200

Cited by 31 publications

(38 citation statements)

References 56 publications

(82 reference statements)

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“…2E), but we did not expect that the modified peptide would alter its binding mode completely in the case of B*27:09, where we observed an entirely unprecedented contact between His116 and pU5 ( Fig. 2F) (Beltrami et al, 2008). This non-canonical conformation bears a close resemblance to the corresponding binding mode of one of the conformations of the unmodified pVIPR peptide in B*27:05 (Fig.…”

Section: X-ray Crystallographic Studiesmentioning

confidence: 83%

“…The interpretation of these results is, however, not straightforward, even when detailed structural information is at hand as in the case of the four peptides investigated here ( [Hülsmeyer et al, 2004], [Hülsmeyer et al, 2005b], [Fiorillo et al, 2005] and [Beltrami et al, 2008]). For example, although we can determine if α-helical residues exhibit dynamic differences between the two HLA-B27 subtypes, the IR spectroscopic approach applied by us does not provide hints regarding which part of the molecule could be affected.…”

Section: Further Biophysical Studiesmentioning

confidence: 93%

“…Peptide binding characteristics can be assessed particularly well when the interactive 3D mode is activated by clicking on the figure. The procedure to embed multimedia content (apart from molecular models and structures of zoological specimens, also videos, and audios) into electronic publications has been pioneered by us ( [Kumar et al, 2008], [Kumar et al, 2009a], [Kumar et al, 2009b], [Kumar et al, 2010], , [Ziegler et al, 2009a], [Ziegler et al, 2010b], [Ziegler et al, 2010c], , [Hee et al, 2010] and [Loll et al, 2011]). This development has been welcomed by structural biologists ( [Tyzack, 2008], [Hodis andSussman, 2009] and[Anon., 2009]).…”

Section: Hla Class I Alleles and Autoimmunitymentioning

confidence: 99%

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HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

Uchańska-Ziegler¹,

Loll²,

Fabian³

et al. 2012

European Journal of Cell Biology

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Section: X-ray Crystallographic Studiesmentioning

confidence: 83%

Section: Further Biophysical Studiesmentioning

confidence: 93%

Section: Hla Class I Alleles and Autoimmunitymentioning

confidence: 99%

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HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

Uchańska-Ziegler¹,

Loll²,

Fabian³

et al. 2012

European Journal of Cell Biology

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“…For instance, the formyl group on an Nt-formylated peptide binds to the bottom of the peptide-binding groove of H2-M3 (5); both the glycan and the phosphate moieties of the central region of the glycopeptides (6,7) and the phosphopeptides (8,9), respectively, are exposed to enable TCR binding, and the deimination (citrullination) of arginine on a peptide presented by two HLA-B27 subtypes induces distinct peptide conformations (10). N a -terminal acetylation (Nt-acetylation) is one of the most common PTMs, occurring on the vast majority of eukaryotic proteins.…”

mentioning

confidence: 99%

Nα-Terminal Acetylation for T Cell Recognition: Molecular Basis of MHC Class I–Restricted Nα-Acetylpeptide Presentation

Sun

et al. 2014

The Journal of Immunology

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As one of the most common posttranslational modifications (PTMs) of eukaryotic proteins, Nα-terminal acetylation (Nt-acetylation) generates a class of Nα-acetylpeptides that are known to be presented by MHC class I at the cell surface. Although such PTM plays a pivotal role in adjusting proteolysis, the molecular basis for the presentation and T cell recognition of Nα-acetylpeptides remains largely unknown. In this study, we determined a high-resolution crystallographic structure of HLA (HLA)-B*3901 complexed with an Nα-acetylpeptide derived from natural cellular processing, also in comparison with the unmodified-peptide complex. Unlike the α-amino–free P1 residues of unmodified peptide, of which the α-amino group inserts into pocket A of the Ag-binding groove, the Nα-linked acetyl of the acetylated P1-Ser protrudes out of the groove for T cell recognition. Moreover, the Nt-acetylation not only alters the conformation of the peptide but also switches the residues in the α1-helix of HLA-B*3901, which may impact the T cell engagement. The thermostability measurements of complexes between Nα-acetylpeptides and a series of MHC class I molecules derived from different species reveal reduced stability. Our findings provide the insight into the mode of Nα-acetylpeptide–specific presentation by classical MHC class I molecules and shed light on the potential of acetylepitope-based immune intervene and vaccine development.

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“…Importantly, several of these modified autoantigens are preferentially processed, presented and recognized by the immune system contributing to the development of autoimmunity (66,67). PTMs associated with apoptotic cell death increase the immunogenicity of self antigens and predispose to autoimmunity.…”

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confidence: 99%

Autoimmune Consequences of Histone Deimination during Neutrophil Activation

Dwivedi¹

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DEDICATION ABSTRACTTolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or "trap" bacterial pathogens. Neutrophil extracellular traps (NETs), as these structures are known, generate an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalized by host phagocytes during inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance.To test the hypothesis that NETs can lead to autoimmunity, we measured autoantibodies to deiminated histones in human autoimmune disorders. We detected autoantibodies to deiminated histones in Felty's syndrome (FS) patients, whereas autoantibodies from Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) patients did not distinguish deiminated from non-deiminated histones. FS autoantibodies colocalized with deiminated histone H3 in LPS-treated neutrophils suggesting activated neutrophils as the source of autoantigens. In addition, we identified and characterized deimination of linker histone H1 and found rare autoantibodies to deiminated H1 in SLE and Sjogren's syndrome patients. We also studied sera of autoimmune lupus prone mice to determine if they would recognize deiminated histones and found that deimination represses binding of murine lupus autoantibodies to histones. The inability of immunoglobin from sera of lupus mice to recognize deiminated histones suggests the presence of effective tolerance to NET components released during innate neutrophil response to infections. Our finding of antibodies to deiminated histones in Felty's syndrome supports the idea that tolerance to deiminated histones is compromised only in exceptional circumstances. Understanding the tolerance mechanism to deiminated histones and how they are compromised in patients could be useful to design strategies for the prevention and treatment of many autoimmune disorders.vi AutoimmunityIn 1901 Erhlich coined the term "Horror Autotoxicus" to explain "the unwillingness of the organism to endanger itself by formation of toxic autoantibodies". He found that immunizing goats...

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

Cited by 31 publications

References 56 publications

HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

Nα-Terminal Acetylation for T Cell Recognition: Molecular Basis of MHC Class I–Restricted Nα-Acetylpeptide Presentation

Autoimmune Consequences of Histone Deimination during Neutrophil Activation

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