Seminar

Structural basis for complement Factor I control and its disease associated sequence polymorphisms

Pietro Roversi, PhD

The complement system is a key component of innate immune defence, coordinating inflammation with innate and adaptive responses, both in infection and in homeostasis. 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). Factor I is seen to be 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 non-catalytic 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 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.