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Analogous Interactions in Initiating Complexes of the Classical and Lectin Pathways of Complement¹

Anna E. Phillips^2,*, Julia Toth^2,*, Alister W. Dodds, Umakhanth Venkatraman Girija^*,, Christopher M. Furze^*, Eleni Pala^*, Robert B. Sim, Kenneth B. M. Reid, Wilhelm J. Schwaeble^*, Ralf Schmid, Anthony H. Keeble^*, and Russell Wallis^3,*,

^* Department of Infection, Immunity and Inflammation and Department of Biochemistry, University of Leicester, Leicester, United Kingdom; and Department of Biochemistry, Medical Research Council Immunochemistry Unit, University of Oxford, Oxford, United Kingdom

The classical and lectin pathways of complement activation neutralize pathogens and stimulate key immunological processes. Both pathways are initiated by collagen-containing, soluble pattern recognition molecules associated with specific serine proteases. In the classical pathway, C1q binds to Ab-Ag complexes or bacterial surfaces to activate C1r and C1s. In the lectin pathway, mannan-binding lectin and ficolins bind to carbohydrates on pathogens to activate mannan-binding lectin-associated serine protease 2. To characterize the interactions leading to classical pathway activation, we have analyzed binding between human C1q, C1r, and C1s, which associate to form C1, using full-length and truncated protease components. We show that C1r and C1s bind to C1q independently. The CUB1-epidermal growth factor fragments contribute most toward binding, but CUB2 of C1r, but not of C1s, is also important. Each C1rs tetramer presents a total of six binding sites, one for each of the collagenous domains of C1q. We also demonstrate that subcomponents of the lectin and classical pathways cross-interact. Thus, although the stoichiometries of complexes differ, interactions are analogous, with equivalent contacts between recognition and protease subcomponents. Importantly, these new data are contrary to existing models of C1 and enable us to propose a new model using mannan-binding lectin-mannan-binding lectin-associated serine protease interactions as a template.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding for this work was supplied by Grant 077400 from the Wellcome Trust and Grant G0501425 from the Medical Research Council. R.W. is a Research Council U.K. Academic Fellow. A.H.K. is a Welcome Trust Value in People Award Fellow.

² A.E.P. and J.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Russell Wallis, Departments of Infection, Immunity and Inflammation and Biochemistry, Maurice Shock Building, University of Leicester, PO Box 138, Leicester, LE1 9HN U.K. E-mail address: rw73{at}le.ac.uk

⁴ Abbreviations used in this paper: MBL, mannan-binding lectin; MASP, MBL-associated serine protease; CUB, domain found in complement component C1r/C1s, Uegf, and bone morphogenic protein 1; EGF, epidermal growth factor; CCP, complement control protein; SP, serine protease.

⁵ The online version of this article contains supplemental material.