ArticleJournal of immunology (Baltimore, Md. : 1950)2015
Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity.
Article in Journal of immunology (Baltimore, Md. : 1950), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- Exosomal-complement system activation in preeclampsia.The journal of obstetrics and gynaecology research · 2025Review
- Article
- Electrochemical nano-biosensor based on electrospun indium zinc oxide nanofibers for the determination of complement component 3 protein.Mikrochimica acta · 2023Article
- Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors.Nature communications · 2022Article
- Multifaceted Activities of Seven Nanobodies against Complement C4b.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Computational analysis of complement inhibitor compstatin using molecular dynamics.Journal of molecular modeling · 2020Article
- Complement C3 gene polymorphisms are associated with lipid levels, but not the risk of coronary artery disease: a case-control study.Lipids in health and disease · 2019Article
- Revealing Unknown Protein Structures Using Computational Conformational Sampling Guided by Experimental Hydrogen-Exchange Data.International journal of molecular sciences · 2018Article
- The renaissance of complement therapeutics.Nature reviews. Nephrology · 2018Review
- Functional Characterization of Alternative and Classical Pathway C3/C5 Convertase Activity and Inhibition Using Purified Models.Frontiers in immunology · 2018Article
- Native State of Complement Protein C3d Analysed via Hydrogen Exchange and Conformational Sampling.International journal of computational biology and drug design · 2018Article
- Coarse-Grained Conformational Sampling of Protein Structure Improves the Fit to Experimental Hydrogen-Exchange Data.Frontiers in molecular biosciences · 2017Article
- Characterization of Embryo Transcriptome of Gynogenetic Olive Flounder Paralichthys olivaceus.Marine biotechnology (New York, N.Y.) · 2016Article
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
The plasma protein C3 is a central element in the activation and effector functions of the complement system. A hereditary dysfunction of C3 that prevents complement activation via the alternative pathway (AP) was described previously in a Swedish family, but its genetic cause and molecular consequences have remained elusive. In this study, we provide these missing links by pinpointing the dysfunction to a point mutation in the β-chain of C3 (c.1180T > C; p.Met(373)Thr). In the patient's plasma, AP activity was completely abolished and could only be reconstituted with the addition of normal C3. The M373T mutation was localized to the macroglobulin domain 4 of C3, which contains a binding site for the complement inhibitor compstatin and is considered critical for the interaction of C3 with the AP C3 convertase. Structural analyses suggested that the mutation disturbs the integrity of macroglobulin domain 4 and induces conformational changes that propagate into adjacent regions. Indeed, C3 M373T showed an altered binding pattern for compstatin and surface-bound C3b, and the presence of Thr(373) in either the C3 substrate or convertase-affiliated C3b impaired C3 activation and opsonization. In contrast to known gain-of-function mutations in C3, patients affected by this loss-of-function mutation did not develop familial disease, but rather showed diverse and mostly episodic symptoms. Our study therefore reveals the molecular mechanism of a relevant loss-of-function mutation in C3 and provides insight into the function of the C3 convertase, the differential involvement of C3 activity in clinical conditions, and some potential implications of therapeutic complement inhibition.
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