Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses

Xue, Xiaoguang and Wu, Jin and Ricklin, Daniel and Forneris, Federico and Di Crescenzio, Patrizia and Schmidt, Christoph Q. and Granneman, Joke and Sharp, Thomas H. and Lambris, John D. and Gros, Piet. (2017) Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses. Nature Structural and Molecular Biology, 24. pp. 643-651.

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The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Ricklin, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Oct 2017 10:26
Deposited On:19 Oct 2017 10:26

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