REPLY TO MORTENSEN ET AL: The zymogen form of complement component C1

In reply to a comment of their study, Almitairi et al explain their model of zymogen C1. The model was assembled from overlapping crystal structures with constraints imposed by known interactions. The starting point was the protease subcomponent, C1r2C1s2, which comprises two antiparallel C1r-C1s dimers (mediated via CUB1-EGF-CUB2 contacts) linked through a central interaction between the CCP1-CCP2-SP domains of C1r. During C1 assembly, C1r2C1s2 folds-up, so the CUB1-EGF-CUB2 domains bind to the collagenous stems of C1q. Almitairi et al propose that C1r-C1r interactions are maintained in zymogen C1, preventing one C1r polypeptide from activating its partner. Activation is driven by separation of C1r arms when C1q binds to a surface. Their model is compatible with solution, structural, and kinetic data, suggesting intracomplex activation, and incorporates all known interactions: C1r CCP1-CCP2-SP dimers, C1r/C1s CUB1-EGF-CUB2 dimers, and CUB-C1q contacts.