biostudies-literatureXue XEuropean Research CouncilNIAID NIH HHS643-651https://www.ebi.ac.uk/biostudies/studies/S-EPMC5773341biostudies-literatureUnknown24(8)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 therNature structural & molecular biologyRegulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses.PMC5773341R01 AI030040N01 AI030040P01 AI068730283570602699233229Granneman JWu JSchmidt CQSharp THForneris FDi Crescenzio PLambris JDGros PXue XRicklin DfalseRegulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses.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 ther2017-01-01T00:00:00Z2017 Aug2026-05-03T10:20:17.623Z2019-03-26T23:48:50ZS-EPMC57733412867166410.1038/nsmb.3427