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Coexistence of Closed and Open Conformations of Complement Factor B in the Alternative Pathway C3bB(Mg²⁺) Proconvertase^1,2

Eva Torreira,^* Agustín Tortajada,^* Tamara Montes,^* Santiago Rodríguez de Córdoba,^3* and Oscar Llorca^3*

*Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras and Instituto Reina Sofía de Investigaciones Nefrológicas. Ramiro de Maeztu 9, Madrid, Spain

Complement factor B (fB) circulates in plasma as a proenzyme that, upon binding to C3b in the presence of Mg²⁺, is cleaved by factor D to produce Ba and Bb fragments. Activated Bb remains bound to C3b organizing the alternative pathway C3 convertase (C3bBb). Recently, we have visualized the stable C3bB(Ni²⁺) proconvertase using electron microscopy, revealing a large conformational change of the C3b-bound fB likely exposing the fD-cleavage site. In contrast, the crystal structure of the proconvertase formed by human fB and the cobra venom factor reveals fB in the closed conformation of the proenzyme. In this study, we have used single-particle electron microscopy and image processing to examine the C3bB(Mg²⁺) proconvertase. We describe two C3bB(Mg²⁺) conformations, one resembling cobra venom factor, likely representing the loading state of fB to C3b, and another identical with C3bB(Ni²⁺). These data illustrate the coexistence of C3b-bound fB in closed and open conformations that either exist in equilibrium or represent structural transitions during the assembly of the C3bB proconvertase.

Correspondence: ³ Address correspondence and reprint requests to Dr. Santiago Rodríguez de Córdoba or Dr. Oscar Llorca, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. E-mail addresses: srdecordoba{at}cib.csic.es or ollorca{at}cib.csic.es

¹ This work has been supported by projects SAF2008-00451 (to O.L.) and SAF2008-00226 (to S.R.C.) from the Spanish Ministry of Science, and the "Red Temática de Investigación Cooperativa en Cáncer (RTICC), RD06/0020/1001" from the "Instituto de Salud Carlos III" (to O.L.). O.L. group is additionally supported by the Human Frontiers Science Program (RGP39/2008) and the Autonomous Region of Madrid (CAM S-BIO-0214-2006). SRC group is additionally supported by CIBERER (INTRA/08/738.2) and the Instituto Reina Sofía de Investigaciones Nefrológicas.

² All authors contributed equally to this work.