1. Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses
- Author
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Patrizia Di Crescenzio, Thomas H. Sharp, John D. Lambris, Federico Forneris, Piet Gros, Jin Wu, Daniel Ricklin, Joke C.M. Granneman, Xiaoguang Xue, and Christoph Q. Schmidt
- Subjects
0301 basic medicine ,Models, Molecular ,Protein Conformation ,Immunology ,Regulator ,chemical and pharmacologic phenomena ,Complement factor I ,Biology ,Crystallography, X-Ray ,Article ,03 medical and health sciences ,Scissile bond ,0302 clinical medicine ,Protein structure ,Structural Biology ,Humans ,Molecular Biology ,X-ray crystallography ,Proteases ,CUB domain ,Complement system ,Cell biology ,030104 developmental biology ,Complement Factor I ,Factor H ,Complement Factor H ,Complement C3b ,Proteolysis ,iC3b ,030215 immunology ,Protein Binding - Abstract
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.
- Published
- 2017