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.
Department of Infection, University of Leicester, Leicester LE1 9HN, United Kingdom.
Umakhanth
U
Venkatraman Girija
Alexandre R
AR
Gingras
Jamie E
JE
Marshall
Roshni
R
Panchal
Md Arif
MA
Sheikh
James A J
JA
Harper
Péter
P
Gál
Wilhelm J
WJ
Schwaeble
Daniel A
DA
Mitchell
Peter C E
PC
Moody
Russell
R
Wallis
D000818:Animals; D016466:CHO Cells; D002846:Chromatography, Affinity; D002850:Chromatography, Gel; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D003172:Complement C1 / Q000737:chemistry*; D015922:Complement C1q / Q000737:chemistry* / Q000378:metabolism; D003173:Complement C1s / Q000737:chemistry* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003460:Crystallization; D004926:Escherichia coli; D007113:Immunity, Innate / Q000276:immunology*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
D003172:Complement C1; D015922:Complement C1q; D003173:Complement C1s
innate immunity; structural biology