Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding.

Autoantibodies / chemistry Cysteine / chemistry Disulfides / chemistry Immunoglobulin G / chemistry Microscopy, Atomic Force Models, Molecular Protein Binding / immunology Protein Conformation Protein Folding Protein Interaction Domains and Motifs Structure-Activity Relationship beta 2-Glycoprotein I / chemistry

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
25 02 2021
Historique:
received: 10 10 2020
accepted: 10 02 2021
entrez: 26 2 2021
pubmed: 27 2 2021
medline: 15 12 2021
Statut: epublish

Résumé

Beta-2-glycoprotein I (β2GPI) is a blood protein and the major antigen in the autoimmune disorder antiphospholipid syndrome (APS). β2GPI exists mainly in closed or open conformations and comprises of 11 disulfides distributed across five domains. The terminal Cys288/Cys326 disulfide bond at domain V has been associated with different cysteine redox states. The role of this disulfide bond in conformational dynamics of this protein has not been investigated so far. Here, we report on the enzymatic driven reduction by thioredoxin-1 (recycled by Tris(2-carboxyethyl)phosphine; TCEP) of β2GPI. Specific reduction was demonstrated by Western blot and mass spectrometry analyses confirming majority targeting to the fifth domain of β2GPI. Atomic force microscopy images suggested that reduced β2GPI shows a slightly higher proportion of open conformation and is more flexible compared to the untreated protein as confirmed by modelling studies. We have determined a strong increase in the binding of pathogenic APS autoantibodies to reduced β2GPI as demonstrated by ELISA. Our study is relevant for understanding the effect of β2GPI reduction on the protein structure and its implications for antibody binding in APS patients.

Identifiants

DOI: 10.1038/s41598-021-84021-2 PMID: 33633190 PMC: PMC7907366
pubmed: 33633190
doi: 10.1038/s41598-021-84021-2
pii: 10.1038/s41598-021-84021-2
pmc: PMC7907366
doi:

Substances chimiques

Autoantibodies 0
Disulfides 0
Immunoglobulin G 0
beta 2-Glycoprotein I 0
Cysteine K848JZ4886

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

4542

Subventions

Organisme : Medical Research Council
ID : MR/P017371/1
Pays : United Kingdom
Organisme : MRF
ID : MRF_MRF-057-0004-RG-MCDO-C0800
Pays : United Kingdom

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Auteurs

Ina Buchholz (I)

Institute of Biochemistry, University of Greifswald, Greifswald, Germany.
ZIK HIKE, University of Greifswald, Greifswald, Germany.

Thomas McDonnell (T)

Division of Biochemical Engineering, Bernard Katz Institute, University College London, London, UK.

Peter Nestler (P)

Institute of Physics, University of Greifswald, Greifswald, Germany.

Sudarat Tharad (S)

Institute for Biophysics, University of Natural Resources and Life Sciences Vienna, Vienna, Austria.

Martin Kulke (M)

Institute of Biochemistry, University of Greifswald, Greifswald, Germany.

Anna Radziszewska (A)

Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH, London, UK.
Division of Medicine, Centre for Rheumatology, University College London, London, UK.

Vera M Ripoll (VM)

Division of Medicine, Centre for Rheumatology, University College London, London, UK.

Frank Schmidt (F)

Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
Proteomics Core, Weill Cornell Medicine-Qatar, Doha, Qatar.

Elke Hammer (E)

Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.

Jose L Toca-Herrera (JL)

Institute for Biophysics, University of Natural Resources and Life Sciences Vienna, Vienna, Austria.

Anisur Rahman (A)

Division of Medicine, Centre for Rheumatology, University College London, London, UK. anisur.rahman@ucl.ac.uk.

Mihaela Delcea (M)

Institute of Biochemistry, University of Greifswald, Greifswald, Germany. delceam@uni-greifswald.de.
ZIK HIKE, University of Greifswald, Greifswald, Germany. delceam@uni-greifswald.de.
DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany. delceam@uni-greifswald.de.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Autoanticorps › Specific domain V reduction of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés soufrés › Cystéine › Specific domain V reduction of...
questionsmedicales.fr › Composés chimiques organiques › Composés du soufre › Sulfures › Disulfures › Specific domain V reduction of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Isotypes des immunoglobulines › Immunoglobuline G › Specific domain V reduction of...
questionsmedicales.fr › Techniques d'investigation › Microscopie à sonde à balayage › Microscopie à force atomique › Specific domain V reduction of...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Specific domain V reduction of...
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Specific domain V reduction of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Specific domain V reduction of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Pliage des protéines › Specific domain V reduction of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Motifs et domaines d'intéraction protéique › Specific domain V reduction of...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Specific domain V reduction of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Glycoprotéines › bêta 2-Glycoprotéine I › Specific domain V reduction of...