dc.contributor.author
Loll, Bernhard
dc.contributor.author
Rückert, Christine
dc.contributor.author
Uchanska-Ziegler, Barbara
dc.contributor.author
Ziegler, Andreas
dc.date.accessioned
2020-02-14T11:38:28Z
dc.date.available
2020-02-14T11:38:28Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/26673
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-26430
dc.description.abstract
The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
X-ray structure
en
dc.subject
peptide binding modes
en
dc.subject
conformational flexibility
en
dc.subject
T cell selection
en
dc.subject
central tolerance
en
dc.subject
molecular mimicry
en
dc.subject
ankylosing spondylitis
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::540 Chemie::540 Chemie und zugeordnete Wissenschaften
dc.title
Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
179
dcterms.bibliographicCitation.doi
10.3389/fimmu.2020.00179
dcterms.bibliographicCitation.journaltitle
Frontiers in Immunology
dcterms.bibliographicCitation.volume
11
dcterms.bibliographicCitation.url
https://doi.org/10.3389/fimmu.2020.00179
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Chemie und Biochemie
![Dieser Normdateneintrag wurde von einer Benutzerin oder einem Benutzer als gültig bestätigt.](/cache_202e45ad85b55efaeb29160f63cd3f3b/themes/FuCD/images/authority_control/invisible.gif)
refubium.note.author
Die Publikation wurde aus Open Access Publikationsgeldern der Freien Universität Berlin gefördert.
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1664-3224
dcterms.isPartOf.zdb
2606827-8