Venkatraman Girija, Umakhanth, Gingras, Alexandre R, Marshall, Jamie E, Panchal, Roshni, Sheikh, Md Arif, Gál, Péter, Schwaeble, Wilhelm J, Mitchell, Daniel A, Moody, Peter C E and Wallis, Russell (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 Academy of Sciences, 110 (34). pp. 13916-13920. ISSN 0027-8424
Full text not available from this repository.Abstract
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 Ca2+-coordinating residues. The data explain the Ca2+-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.
Item Type: | Article |
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Schools and Departments: | School of Life Sciences > Sussex Centre for Genome Damage and Stability |
Depositing User: | MD Arif Sheikh |
Date Deposited: | 07 May 2015 11:50 |
Last Modified: | 07 May 2015 11:50 |
URI: | http://sro.sussex.ac.uk/id/eprint/53898 |