Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding
Abstract 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...
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2021
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oai:doaj.org-article:ab52dc10ebec4e0c9e466f4231064c672021-12-02T13:20:01ZSpecific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding10.1038/s41598-021-84021-22045-2322https://doaj.org/article/ab52dc10ebec4e0c9e466f4231064c672021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84021-2https://doaj.org/toc/2045-2322Abstract 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.Ina BuchholzThomas McDonnellPeter NestlerSudarat TharadMartin KulkeAnna RadziszewskaVera M. RipollFrank SchmidtElke HammerJose L. Toca-HerreraAnisur RahmanMihaela DelceaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021) |
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Medicine R Science Q Ina Buchholz Thomas McDonnell Peter Nestler Sudarat Tharad Martin Kulke Anna Radziszewska Vera M. Ripoll Frank Schmidt Elke Hammer Jose L. Toca-Herrera Anisur Rahman Mihaela Delcea Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding |
| description |
Abstract 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. |
| format |
article |
| author |
Ina Buchholz Thomas McDonnell Peter Nestler Sudarat Tharad Martin Kulke Anna Radziszewska Vera M. Ripoll Frank Schmidt Elke Hammer Jose L. Toca-Herrera Anisur Rahman Mihaela Delcea |
| author_facet |
Ina Buchholz Thomas McDonnell Peter Nestler Sudarat Tharad Martin Kulke Anna Radziszewska Vera M. Ripoll Frank Schmidt Elke Hammer Jose L. Toca-Herrera Anisur Rahman Mihaela Delcea |
| author_sort |
Ina Buchholz |
| title |
Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding |
| title_short |
Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding |
| title_full |
Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding |
| title_fullStr |
Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding |
| title_full_unstemmed |
Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding |
| title_sort |
specific domain v reduction of beta-2-glycoprotein i induces protein flexibility and alters pathogenic antibody binding |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/ab52dc10ebec4e0c9e466f4231064c67 |
| work_keys_str_mv |
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