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EMBO J. 2017 Apr 13;36(8):1084-1099. doi: 10.15252/embj.201696173. Epub 2017 Mar 6.

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

Author information

1
Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.
2
INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
3
Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
4
Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
5
Assistance Publique - Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
6
Centre d'études des déficits immunitaires, CHU Paris - Hôpital Necker-Enfants Malades, Paris, France.
7
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
8
Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
9
Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark gra@mbg.au.dk.

Abstract

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.

KEYWORDS:

alternative pathway; complement; deficiency; properdin; structure

PMID:
28264884
PMCID:
PMC5391138
DOI:
10.15252/embj.201696173
[Indexed for MEDLINE]
Free PMC Article

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