Title : Structural basis for
complement factor I control and its disease-associated sequence polymorphisms
Abstract :
- 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