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

journal contribution
posted on 2023-06-08, 20:42 authored by Umakhanth Venkatraman Girija, Alexandre R Gingras, Jamie E Marshall, Roshni Panchal, Md Arif Sheikh, Péter Gál, Wilhelm J Schwaeble, Daniel A Mitchell, Peter C E Moody, Russell Wallis
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.

History

Publication status

  • Published

Journal

Proceedings of the National Academy of Sciences

ISSN

0027-8424

Publisher

National Academy of Sciences

Issue

34

Volume

110

Page range

13916-13920

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-05-07

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