2024-03-28T12:13:51Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/95222021-12-27T16:43:34Zcom_10261_86com_10261_1col_10261_339
3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase
Torreira, Eva
Tortajada, Agustín
Montes, Tamara
Rodríguez de Córdoba, Santiago
Llorca, Óscar
C3 convertase
Electron microscopy
Factor B
6 pages, 4 figures.-- Supporting information (SI materials and methods, 6 pages) available at: http://www.pnas.org/content/suppl/2009/01/09/0810860106.DCSupplemental/0810860106SI.pdf
Generation of the alternative pathway C3-convertase, the central amplification enzyme of the complement cascade, initiates by the binding of factor B (fB) to C3b to form the proconvertase, C3bB. C3bB is subsequently cleaved by factor D (fD) at a single site in fB, producing Ba and Bb fragments. Ba dissociates from the complex, while Bb remains bound to C3b, forming the active alternative pathway convertase, C3bBb. Using single-particle electron microscopy we have determined the 3-dimensional structures of the C3bB and the C3bBb complexes at ≈27Å resolution. The C3bB structure shows that fB undergoes a dramatic conformational change upon binding to C3b. However, the C3b-bound fB structure was easily interpreted after independently fitting the atomic structures of the isolated Bb and Ba fragments. Interestingly, the divalent cation-binding site in the von Willebrand type A domain in Bb faces the C345C domain of C3b, whereas the serine-protease domain of Bb points outwards. The structure also shows that the Ba fragment interacts with C3b separately from Bb at the level of the α′NT and CUB domains. Within this conformation, the long and flexible linker between Bb and Ba is likely exposed and accessible for cleavage by fD to form the active convertase, C3bBb. The architecture of the C3bB and C3bBb complexes reveals that C3b could promote cleavage and activation of fB by actively displacing the Ba domain from the von Willebrand type A domain in free fB. These structures provide a structural basis to understand fundamental aspects of the activation and regulation of the alternative pathway C3-convertase.
This work has been supported by projects SAF2005–00775 (to O.L.), SAF2008–00451 (to O.L.), SAF2005–0913 and SAF2008–00226 (to S.R.d.C.)
from the Spanish Ministry of Science, CAMS-BIO-0214–2006 (to O.L.) from the Autonomous Region of Madrid, and RD06/0020/1001 (to O.L.) of the Red Temática Investigación Cooperativa en Cáncer from the Instituto Carlos III. O.L.’s group is additionally supported by the Human Frontiers Science Program (RGP39/2008). S.R.d.C.’s group is additionally supported by Centro de
Investigación Biomédica en Red de Enfermedades Raras (INTRA/08/738.2) and the Fundacion Renal Iñigo Alvarez de Toledo.
Peer reviewed
2009-01-09
artículo
http://purl.org/coar/resource_type/c_6501
Proc. Natl. Acad. Sci. USA 106(3): 882-887 (2009)
0027-8424
http://hdl.handle.net/10261/9522
10.1073/pnas.0810860106
19136636
en
http://dx.doi.org/10.1073/pnas.0810860106
open
National Academy of Sciences (U.S.)