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Structural Organization and Zn²⁺-dependent Subdomain Interactions Involving Autoantigenic Epitopes in the Ring-B-box-Coiled-coil (RBCC) Region of Ro52

Title data

Hennig, Janosch ; Ottosson, Lars ; Andrésen, Cecilia ; Horvath, Linn ; Kuchroo, Vijay K. ; Broo, Klas ; Wahren-Herlenius, Marie ; Sunnerhagen, Maria:
Structural Organization and Zn²⁺-dependent Subdomain Interactions Involving Autoantigenic Epitopes in the Ring-B-box-Coiled-coil (RBCC) Region of Ro52.
In: The Journal of Biological Chemistry. Vol. 280 (2005) Issue 39 . - pp. 33250-33261.
ISSN 0021-9258
DOI: https://doi.org/10.1074/jbc.M503066200

Abstract in another language

Ro52 is one of the major autoantigens targeted in the autoimmune disease Sjögren syndrome. By sequence similarity, Ro52 belongs to the RING-B-box-coiled-coil (RBCC) protein family. Disease-related antibodies bind Ro52 in a conformation-dependent way both in the coiled-coil region and in the Zn2+-binding Ring-B-box region. Primarily associated with Sjögren syndrome, Ro52 autoantibodies directed to a specific, partially structured epitope in the coiled-coil region may also induce a congenital heart block in the fetus of pregnant Ro52-positive mothers. To improve our understanding of the pathogenic effects of autoantibody binding to the Zn2+-binding region, a multianalytical mapping of its structural, biophysical, and antigenic properties is presented. Structure content and ligand binding of subregions, dissected by peptide synthesis and subcloning, were analyzed by fluorescence and circular dichroism spectroscopy. A novel matrix-assisted laser desorption ionization time-of-flight mass spectrometry strategy for time-resolved proteolysis experiments of large protein domains was developed to facilitate analysis and to help resolve the tertiary arrangement of the entire RBCC subregion. The linker region between the RING and B-box motifs is crucial for full folding, and Zn2+ affinity of the RING-B-box region is further protected in the entire RBCC region and appears to interact with the coiled-coil region. Murine monoclonal antibodies raised toward the RING-B-box region were primarily directed toward the linker, further supporting a highly functional role for the linker in a cellular environment. Taken together with our previous analysis of autoantigenic epitopes in the coiled-coil region, localization of autoantigenic epitopes in Ro52 appears closely related to molecular functionalities.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry with an Emphasis on Biophysical Chemistry > Chair Biochemistry with an Emphasis on Biophysical Chemistry - Univ.-Prof. Dr. Janosch Hennig
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 08 Oct 2021 09:27
Last Modified: 08 Oct 2021 09:27
URI: https://eref.uni-bayreuth.de/id/eprint/67258