Structures of complement component C3 provide insights into the function and evolution of immunity.
Bert J C Janssen1, Eric G Huizinga, Hans C A Raaijmakers
1Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Nature
|September 24, 2005
Summary
The complement system
Area of Science:
- Immunology and Biochemistry
Background:
- The mammalian complement system is crucial for innate and adaptive immunity.
- Component C3 is central to all complement pathways, mediating inflammation and target elimination.
Purpose of the Study:
- To elucidate the structural basis of complement component C3 activation and function.
- To investigate the evolutionary origins of alpha2-macroglobulin superfamily proteins.
Main Methods:
- X-ray crystallography was used to determine the structures of native C3 and its fragment C3c.
- Bioinformatic analysis was employed to study protein domain evolution.
Main Results:
- Crystal structures revealed thirteen domains in C3, with nine previously unpredicted.
- The structures suggest an evolutionary origin from a core of eight homologous domains.
- A dual mechanism was identified that prevents premature hydrolysis of the C3 thioester group.
- Significant conformational changes in the alpha-chain indicate a conformation-dependent activation mechanism.
Conclusions:
- The findings provide unprecedented insights into the activation, regulation, and function of complement C3.
- The study sheds light on the evolution of the alpha2-macroglobulin family.
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