title: Functional and structural insight into properdin control of complement alternative pathway amplification.
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 oligomerizationin vivowhile our monomers enable detailed structural insight paving the way for novel modulators of complement.
authors.affiliation: Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.
authors.forename: Dennis V
authors.initials: DV
authors.lastname: Pedersen
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
authors.forename: Lubka
authors.initials: L
authors.lastname: Roumenina
authors.affiliation: Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.
authors.forename: Rasmus K
authors.initials: RK
authors.lastname: Jensen
authors.affiliation: Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark.
authors.forename: Trine Af
authors.initials: TA
authors.lastname: Gadeberg
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marinozzi
authors.affiliation: Centre d'études des déficits immunitaires, CHU Paris - Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
authors.forename: Tania
authors.initials: T
authors.lastname: Rybkine
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Uffe Bs
authors.initials: UB
authors.lastname: Sørensen
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors.forename: Cordula
authors.initials: C
authors.lastname: Stover
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Assistance Publique - Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.affiliation: Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark gra@mbg.au.dk.
authors.forename: Gregers R
authors.identifier: 0000-0001-6292-3319
authors.initials: GR
authors.lastname: Andersen
mesh_terms: D019943:Amino Acid Substitution; D050577:Complement C3-C5 Convertases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D011414:Properdin / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D055503:Protein Multimerization
chemical_list: D011414:Properdin; D050577:Complement C3-C5 Convertases
keywords: alternative pathway; complement; deficiency; properdin; structure