Functional and structural insight into properdin control of complement alternative pathway amplification

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DOI

  • Dennis V Pedersen
  • Lubka T Roumenina, Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • ,
  • Rasmus K Jensen
  • Trine Af Gadeberg
  • Chiara Marinozzi, Assistance Publique - Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
  • ,
  • Capucine Picard, Centre d'études des déficits immunitaires, CHU Paris - Hôpital Necker-Enfants Malades, Paris, France.
  • ,
  • Tania Rybkine, Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • ,
  • Steffen Thiel
  • Uffe Bs Sørensen
  • Cordula Stover, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
  • ,
  • Veronique Fremeaux-Bacchi, Assistance Publique - Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
  • ,
  • Gregers R Andersen

Properdin (FP) is an essential positive regulator of the complement alternative pathway (AP) providing stabilization of the C3 and C5 convertases, but its oligomeric nature challenges structural analysis. We describe here a novel FP deficiency (E244K) caused by a single point mutation which results in a very low level of AP activity. Recombinant FP E244K is monomeric, fails to support bacteriolysis, and binds weakly to C3 products. We compare this to a monomeric unit excised from oligomeric FP, which is also dysfunctional in bacteriolysis but binds the AP proconvertase, C3 convertase, C3 products and partially stabilizes the convertase. The crystal structure of such a FP-convertase complex suggests that the major contact between FP and the AP convertase is mediated by a single FP thrombospondin repeat and a small region in C3b. Small angle X-ray scattering indicates that FP E244K is trapped in a compact conformation preventing its oligomerization. Our studies demonstrate an essential role of FP oligomerization in vivo while our monomers enable detailed structural insight paving the way for novel modulators of complement.

Original languageEnglish
JournalE M B O Journal
Volume36
Issue8
ISSN0261-4189
DOIs
Publication statusPublished - 2017

    Research areas

  • Journal Article

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