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Science 330 (6012): 1816-1820

Copyright © 2010 by the American Association for the Advancement of Science

Structures of C3b in Complex with Factors B and D Give Insight into Complement Convertase Formation

Federico Forneris,1 Daniel Ricklin,2 Jin Wu,1 Apostolia Tzekou,2 Rachel S. Wallace,1 John D. Lambris,2,* Piet Gros1,*

Abstract: Activation of the complement cascade induces inflammatory responses and marks cells for immune clearance. In the central complement-amplification step, a complex consisting of surface-bound C3b and factor B is cleaved by factor D to generate active convertases on targeted surfaces. We present crystal structures of the pro-convertase C3bB at 4 angstrom resolution and its complex with factor D at 3.5 angstrom resolution. Our data show how factor B binding to C3b forms an open "activation" state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D’s self-inhibitory loop. This concerted proteolytic mechanism, which is cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.

1 Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands.
2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, 401 Stellar Chance, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: p.gros{at}uu.nl (P.G.); lambris{at}upenn.edu (J.D.L.)


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