Structural Basis for the Stabilization of the Complement Alternative Pathway C3 Convertase by Properdin

Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13504-9. doi: 10.1073/pnas.1309618110. Epub 2013 Jul 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • CHO Cells
  • Complement C3-C5 Convertases / immunology*
  • Complement C3b / immunology*
  • Complement Factor B / immunology*
  • Complement Pathway, Alternative / immunology*
  • Cricetinae
  • Cricetulus
  • Immunity, Innate / immunology*
  • Microscopy, Electron, Transmission
  • Models, Immunological*
  • Properdin / immunology
  • Properdin / pharmacology*

Substances

  • Properdin
  • Complement C3b
  • Complement C3-C5 Convertases
  • Complement Factor B