Complement and the Multifaceted Functions of VWA and Integrin I Domains

The recent crystal structure of complement protein component C2a reveals an interface between its VWA and serine protease domains that could not exist in the zymogen C2. The implied change in VWA domain conformation between C2 and C2a differs from that described for other VWA domains, including the I domains in integrins. Here, the remarkable diversity in both conformational regulation and ligand binding among VWA domains that function in complement, hemostasis, cell adhesion, anthrax toxin binding, vesicle transport, DNA break repair, and RNA quality control is reviewed. Finally, implications for metastability of complement convertases are discussed.