Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein
The complement system is one of the first defense lines protecting from invading pathogens. However, it may turn offensive to the body’s own cells and tissues when deregulated by the presence of rare genetic variants that impair physiological regulation and/or provoke abnormal activity of key enzyma...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1061696/full |
| _version_ | 1811197542410485760 |
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| author | Alicja Kuźniewska Marcel Thiel Daria Kowalska Anna Felberg-Miętka Patryk Szynkowski Stanisław Ołdziej Emilia Arjona Ilse Jongerius Ilse Jongerius Santiago Rodriguez de Córdoba Marcin Okrój Aleksandra Urban Aleksandra Urban |
| author_facet | Alicja Kuźniewska Marcel Thiel Daria Kowalska Anna Felberg-Miętka Patryk Szynkowski Stanisław Ołdziej Emilia Arjona Ilse Jongerius Ilse Jongerius Santiago Rodriguez de Córdoba Marcin Okrój Aleksandra Urban Aleksandra Urban |
| author_sort | Alicja Kuźniewska |
| collection | DOAJ |
| description | The complement system is one of the first defense lines protecting from invading pathogens. However, it may turn offensive to the body’s own cells and tissues when deregulated by the presence of rare genetic variants that impair physiological regulation and/or provoke abnormal activity of key enzymatic components. Factor B and complement C2 are examples of paralogs engaged in the alternative and classical/lectin complement pathway, respectively. Pathogenic mutations in the von Willebrand factor A domain (vWA) of FB have been known for years. Despite substantial homology between two proteins and the demonstration that certain substitutions in FB translated to C2 result in analogous phenotype, there was a limited number of reports on pathogenic C2 variants in patients. Recently, we studied a cohort of patients suffering from rare kidney diseases and confirmed the existence of two gain-of-function and three loss-of-function mutations within the C2 gene sequences coding for the vWA domain (amino acids 254-452) or nearly located unstructured region (243-253) of C2 protein. Herein, we report the functional consequences of amino acid substitution of glutamine at position 263. The p.Q263G variant resulted in the gain-of-function phenotype, similarly to a homologous mutation p.D279G in FB. Conversely, the p.Q263P variant found in a patient with C3 glomerulopathy resulted in the loss of C2 function. Our results confirm that the N-terminal part of the vWA domain is a hot spot crucial for the complement C2 function. |
| first_indexed | 2024-04-12T01:16:39Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T01:16:39Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-8d3da185c518499ca4dbe1753d9087512022-12-22T03:53:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.10616961061696Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 proteinAlicja Kuźniewska0Marcel Thiel1Daria Kowalska2Anna Felberg-Miętka3Patryk Szynkowski4Stanisław Ołdziej5Emilia Arjona6Ilse Jongerius7Ilse Jongerius8Santiago Rodriguez de Córdoba9Marcin Okrój10Aleksandra Urban11Aleksandra Urban12Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, SpainDepartment of Pediatric Immunology, Rheumatology, and Infectious Diseases, Emma Children’s Hospital, Amsterdam University Medical Centre, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research, Landsteiner Laboratory, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, NetherlandsDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, SpainDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandInstitute for Cancer Research, Oslo University Hospital, Oslo, NorwayThe complement system is one of the first defense lines protecting from invading pathogens. However, it may turn offensive to the body’s own cells and tissues when deregulated by the presence of rare genetic variants that impair physiological regulation and/or provoke abnormal activity of key enzymatic components. Factor B and complement C2 are examples of paralogs engaged in the alternative and classical/lectin complement pathway, respectively. Pathogenic mutations in the von Willebrand factor A domain (vWA) of FB have been known for years. Despite substantial homology between two proteins and the demonstration that certain substitutions in FB translated to C2 result in analogous phenotype, there was a limited number of reports on pathogenic C2 variants in patients. Recently, we studied a cohort of patients suffering from rare kidney diseases and confirmed the existence of two gain-of-function and three loss-of-function mutations within the C2 gene sequences coding for the vWA domain (amino acids 254-452) or nearly located unstructured region (243-253) of C2 protein. Herein, we report the functional consequences of amino acid substitution of glutamine at position 263. The p.Q263G variant resulted in the gain-of-function phenotype, similarly to a homologous mutation p.D279G in FB. Conversely, the p.Q263P variant found in a patient with C3 glomerulopathy resulted in the loss of C2 function. Our results confirm that the N-terminal part of the vWA domain is a hot spot crucial for the complement C2 function.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1061696/fullcomplement systemconvertaseMIDASmolecular modelingC3 glomerulopathies |
| spellingShingle | Alicja Kuźniewska Marcel Thiel Daria Kowalska Anna Felberg-Miętka Patryk Szynkowski Stanisław Ołdziej Emilia Arjona Ilse Jongerius Ilse Jongerius Santiago Rodriguez de Córdoba Marcin Okrój Aleksandra Urban Aleksandra Urban Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein Frontiers in Immunology complement system convertase MIDAS molecular modeling C3 glomerulopathies |
| title | Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein |
| title_full | Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein |
| title_fullStr | Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein |
| title_full_unstemmed | Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein |
| title_short | Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein |
| title_sort | substitutions at position 263 within the von willebrand factor type a domain determine the functionality of complement c2 protein |
| topic | complement system convertase MIDAS molecular modeling C3 glomerulopathies |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1061696/full |
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