Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation
Complement component C1, the complex that initiates the classical pathway of complement activation, is a 790-kDa assembly formed from the target-recognition subcomponent C1q and the modular proteases C1r and C1s. The proteases are elongated tetramers that become more compact when they bind to the collagen-like domains of C1q. Here, we describe a series of structures that reveal how the subcomponents associate to form C1. A complex between C1s and a collagen-like peptide containing the C1r/C1s-binding motif of C1q shows that the collagen binds to a shallow groove via a critical lysine side chain that contacts Ca(2+)-coordinating residues. The data explain the Ca(2+)-dependent binding mechanism, which is conserved in C1r and also in mannan-binding lectin-associated serine proteases, the serine proteases of the lectin pathway activation complexes. In an accompanying structure, C1s forms a compact ring-shaped tetramer featuring a unique head-to-tail interaction at its center that replicates the likely arrangement of C1r/C1s polypeptides in the C1 complex. Additional structures reveal how C1s polypeptides are positioned to enable activation by C1r and interaction with the substrate C4 inside the cage-like assembly formed by the collagenous stems of C1q. Together with previously determined structures of C1r fragments, the results reported here provide a structural basis for understanding the early steps of complement activation via the classical pathway.
Citation : Venkatraman Girija, U., Gingras, A.R., Marshall, J.E., Panchal, R., Sheikh, M.A. Gál, P., Schwaeble, W.J., Mitchell, D.A. Moody, P.C. and Wallis R. (2013) Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation. Proceedings of the National Acadamy of Science of the U S A. Aug 20; 110 (34), pp. 13916-13920
Research Group : Infectious Disease Research Group
Research Institute : Institute for Allied Health Sciences Research
Peer Reviewed : Yes