Structures of complement component C3 provide insights into the function and evolution of immunity

Bert J. C. Janssen, Eric G. Huizinga, Hans C. A. Raaijmakers, Anja Roos, Mohamed R. Daha, Kristina Nilsson-Ekdahl, Bo Nilsson and Piet Gros ()
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Bert J. C. Janssen: Utrecht University
Eric G. Huizinga: Utrecht University
Hans C. A. Raaijmakers: Utrecht University
Anja Roos: Leiden University Medical Center
Mohamed R. Daha: Leiden University Medical Center
Kristina Nilsson-Ekdahl: University Hospital
Bo Nilsson: University Hospital
Piet Gros: Utrecht University

Nature, 2005, vol. 437, issue 7058, 505-511

Abstract: Abstract The mammalian complement system is a phylogenetically ancient cascade system that has a major role in innate and adaptive immunity. Activation of component C3 (1,641 residues) is central to the three complement pathways and results in inflammation and elimination of self and non-self targets. Here we present crystal structures of native C3 and its final major proteolytic fragment C3c. The structures reveal thirteen domains, nine of which were unpredicted, and suggest that the proteins of the α2-macroglobulin family evolved from a core of eight homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the α-chain, including movement of a critical interaction site through a ring formed by the domains of the β-chain, indicate an unprecedented, conformation-dependent mechanism of activation, regulation and biological function of C3.

Date: 2005
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DOI: 10.1038/nature04005

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