Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 33, Pages 13504-13509Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309618110
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Funding
- Autonomous Region of Madrid [S2010/BMD-2316]
- Ramon Areces Foundation
- Spanish government [SAF2011-22988, SAF2011-26583]
- Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020/1001]
- Fundacion Renal Inigo Alvarez de Toledo
- Seventh Framework Programme European Union Project EURenOmics (European Consortium for High-Throughput Research in Rare Kidney Diseases)
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Complement is an essential component of innate immunity. Its activation results in the assembly of unstable protease complexes, denominated C3/C5 convertases, leading to inflammation and lysis. Regulatory proteins inactivate C3/C5 convertases on host surfaces to avoid collateral tissue damage. On pathogen surfaces, properdin stabilizes C3/C5 convertases to efficiently fight infection. How properdin performs this function is, however, unclear. Using electron microscopy we show that the N- and C-terminal ends of adjacent monomers in properdin oligomers conform a curly vertex that holds together the AP convertase, interacting with both the C345C and vWA domains of C3b and Bb, respectively. Properdin also promotes a large displacement of the TED (thioester-containing domain) and CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domains of C3b, which likely impairs C3-convertase inactivation by regulatory proteins. The combined effect of molecular cross-linking and structural reorganization increases stability of the C3 convertase and facilitates recruitment of fluid-phase C3 convertase to the cell surfaces. Our model explains how properdin mediates the assembly of stabilized C3/C5-convertase clusters, which helps to localize complement amplification to pathogen surfaces.
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