Natural MHC Class I Polymorphism Controls the Pathway of Peptide Dissociation from HLA-B27 Complexes

Winkler, Kathrin; Winter, Anja; Rueckert, Christine; Uchańska-Ziegler, Barbara; Alexiev, Ulrike

doi:10.1529/biophysj.106.096602

Cited by 33 publications

(38 citation statements)

References 33 publications

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“…However, the m9 peptide remains firmly bound to the B*27:05 subtype. The difference in half life of the respective complexes is more than 200-fold, namely ∼1 h (m9-B*27:09) as opposed to about 10 days (m9-B*27:05) (Winkler et al, 2007). This demonstrates how a deeply buried HC residue can affect the dynamic properties of peptide-HLA-B27 complexes and explains why lysine is never found at the C-terminus in peptides eluted from B*27:09 molecules in vivo (López de Castro et al, 2004).…”

Section: X-ray Crystallographic Studiesmentioning

confidence: 97%

“…For IR spectroscopy, the light chain of MHC class I complexes, β 2 m, was labelled in vivo with 13 C and then complexed with unlabelled HLA-B27 HC and selected peptides in vitro ( [Fabian et al, 2008], [Fabian et al, 2010] and [Fabian et al, 2011]). Conversely, for fluorescence spectroscopic experiments, unlabelled HLA-B27 HC and β 2 m were reconstituted with peptides carrying a fluorescent marker ( [Pöhlmann et al, 2004], , [Winkler et al, 2007] and [Narzi et al, 2008]). …”

Section: Production Of Peptide-complexed Hla Class I Moleculesmentioning

confidence: 99%

“…1C) (Hülsmeyer et al, 2002). This results in a pronounced destabilisation of the peptide C-terminus in the B*27:09 subtype, as shown by circular dichroism (CD) spectroscopy and differential scanning calorimetry (DSC) (Hillig et al, 2004) as well as by time-resolved fluorescence depolarisation spectroscopic measurements ( [Pöhlmann et al, 2004] and ), kinetic studies (Winkler et al, 2007), and molecular dynamics simulations ( [Pöhlmann et al, 2004] and [Ziegler et al, 2009a]). However, the m9 peptide remains firmly bound to the B*27:05 subtype.…”

Section: X-ray Crystallographic Studiesmentioning

confidence: 99%

“…There are several techniques that are principally suitable, including fluorescence spectroscopy, MD simulation studies, and in particular nuclear magnetic resonance (NMR) spectroscopy. We have already employed the two former approaches ( [Pöhlmann et al, 2004], [Hülsmeyer et al, 2005b], , [Winkler et al, 2007] and [Narzi et al, 2008]) and have recently embarked on the latter (Schmieder et al, manuscript in preparation).…”

Section: Further Biophysical Studiesmentioning

confidence: 99%

“…In the B*27:09 subtype, however, the salt bridge-mediated contact between the m9 peptide and Asp77 is geometrically unfavourable and does not lead to a firm anchoring of m9 within this subtype's binding groove (Fig. 5B) ( [Hülsmeyer et al, 2002], [Pöhlmann et al, 2004], [Winkler et al, 2007], [Narzi et al, 2008] and [Ziegler et al, 2009a]). Peptide binding characteristics can be assessed particularly well when the interactive 3D mode is activated by clicking on the figure.…”

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: 97%

Section: Production Of Peptide-complexed Hla Class I Moleculesmentioning

confidence: 99%

Section: X-ray Crystallographic Studiesmentioning

confidence: 99%

Section: Further Biophysical Studiesmentioning

confidence: 99%

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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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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Increased Conformational Flexibility of HLA–B*27 Subtypes Associated With Ankylosing Spondylitis

Loll

Fabian

Huser

et al. 2016

Arthritis & Rheumatology

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Objective Dissimilarities in antigen processing and presentation are known to contribute to the differential association of HLA–B*27 subtypes with the inflammatory rheumatic disease ankylosing spondylitis (AS). In support of this notion, previous x‐ray crystallographic data showed that peptides can be displayed by almost identical HLA–B*27 molecules in a subtype‐dependent manner, allowing cytotoxic T lymphocytes to distinguish between these subtypes. For example, a human self‐peptide derived from vasoactive intestinal peptide receptor type 1 (pVIPR; sequence RRKWRRWHL) is displayed in a single conformation by B*27:09 (which is not associated with AS), while B*27:05 (which is associated with AS) presents the peptide in a dual binding mode. In addition, differences in conformational flexibility between these subtypes might affect their stability or antigen presentation capability. This study was undertaken to investigate B*27:04 and B*27:06, another pair of minimally distinct HLA–B*27 subtypes, to assess whether dual peptide conformations or structural dynamics play a role in the initiation of AS. Methods Using x‐ray crystallography, we determined the structures of the pVIPR–B*27:04 and pVIPR–B*27:06 complexes and used isotope‐edited infrared (IR) spectroscopy to probe the dynamics of these HLA–B*27 subtypes. Results As opposed to B*27:05 and B*27:09, B*27:04 (which is associated with AS) displays pVIPR conventionally and B*27:06 (which is not associated with AS) presents the peptide in a dual conformation. Comparison of the 4 HLA–B*27 subtypes using IR spectroscopy revealed that B*27:04 and B*27:05 possess elevated molecular dynamics compared to the nonassociated subtypes B*27:06 and B*27:09. Conclusion Our results demonstrate that an increase in conformational flexibility characterizes the disease‐associated subtypes B*27:04 and B*27:05.

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Natural MHC Class I Polymorphism Controls the Pathway of Peptide Dissociation from HLA-B27 Complexes

Cited by 33 publications

References 33 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

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

Increased Conformational Flexibility of HLA–B*27 Subtypes Associated With Ankylosing Spondylitis

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