Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-08, Vol.110 (34), p.13916-13920
• Main Authors: Girija, Umakhanth Venkatraman, Gingras, Alexandre R., Marshall, Jamie E., Panchal, Roshni, Sheikh, Md. Arif, Gál, Péter, Schwaeble, Wilhelm J., Mitchell, Daniel A., Moody, Peter C. E., Wallis, Russell
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Calcium; CHO Cells; Chromatography, Affinity; Chromatography, Gel; Collagen; Collagens; Complement activation; Complement Activation - genetics; Complement Activation - immunology; Complement C1 - chemistry; Complement C1q - chemistry; Complement C1q - metabolism; Complement C1s - chemistry; Complement C1s - metabolism; Cricetinae; Cricetulus; Crystal structure; Crystallization; Crystals; Dimers; Escherichia coli; Hydrogen bonds; Immunity, Innate - immunology; Lectins; Models, Molecular; Molecular structure; Polypeptides; Proteases; Protein Binding; Protein Conformation; Proteins; Substrates; Zymogens
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1311113110

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.