title: Structural basis for the stabilization of the complement alternative pathway C3 convertase by properdin.
abstract: 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.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
authors.forename: Martín
authors.initials: M
authors.lastname: Alcorlo
authors.forename: Agustín
authors.initials: A
authors.lastname: Tortajada
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
authors.forename: Oscar
authors.initials: O
authors.lastname: Llorca
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D050577:Complement C3-C5 Convertases / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology*; D011415:Complement Factor B / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D006224:Cricetinae; D003412:Cricetulus; D007113:Immunity, Innate / Q000276:immunology*; D046529:Microscopy, Electron, Transmission; D018448:Models, Immunological; D011414:Properdin / Q000276:immunology / Q000494:pharmacology*
chemical_list: D011414:Properdin; D003179:Complement C3b; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B
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