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The complement system is a key component of innate and adaptive immune responses. Complement regulation is critical for prevention and control of disease. We have determined the crystal structure of the complement regulatory enzyme human factor I (fI). FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state despite being fully processed to the mature sequence. Mapping of functional data from mutants of fI onto the structure suggests that this inactive form is maintained by the noncatalytic heavy-chain allosterically modulating activity of the light chain. Once the ternary complex of fI, a cofactor and a substrate is formed, the allosteric inhibition is released, and fI is oriented for cleavage. In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors.

Original publication

DOI

10.1073/pnas.1102167108

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

02/08/2011

Volume

108

Pages

12839 - 12844

Keywords

Allosteric Regulation, Binding Sites, Catalytic Domain, Complement C3b, Complement C4b, Complement Factor I, Crystallization, Crystallography, X-Ray, Enzyme Precursors, Genetic Predisposition to Disease, Glycosylation, Humans, Models, Molecular, Mutation, Polymorphism, Genetic, Protein Binding, Protein Structure, Tertiary