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. The complement system is a key component of innate immunity that kills microorganisms directly. It is evolutionarily ancient, predating the immunoglobulins. The crystal structure of the human complement component C3 has now been determined. As well as revealing some of the mechanisms involved in its immune function, the structure has evolutionary implications for mammalian large multi-domain proteins in general — and it may be the largest protein structure (the longest chain and the most domains) so far determined.

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