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Functional and structural insight into properdin control of complement alternative pathway amplification
Author(s) -
Pedersen Dennis V,
Roumenina Lubka,
Jensen Rasmus K,
Gadeberg Trine AF,
Marinozzi Chiara,
Picard Capucine,
Rybkine Tania,
Thiel Steffen,
Sørensen Uffe BS,
Stover Cordula,
FremeauxBacchi Veronique,
Andersen Gregers R
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201696173
Subject(s) - properdin , c3 convertase , alternative complement pathway , biology , complement system , monomer , antiparallel (mathematics) , biochemistry , trimer , microbiology and biotechnology , biophysics , dimer , immunology , chemistry , antibody , physics , organic chemistry , quantum mechanics , magnetic field , polymer
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.