期刊
EMBO JOURNAL
卷 36, 期 8, 页码 1084-1099出版社
WILEY
DOI: 10.15252/embj.201696173
关键词
alternative pathway; complement; deficiency; properdin; structure
资金
- Lundbeck foundation centers LUNA and BRAINSTRUC, Danscatt [R155-2015-2666]
- Danish Research Council for Independent Research [1323-00107B, 4181-00137B]
- Novo Nordisk Foundation [12261]
- French National Research Agency [ANR-15-CE15-0001, ANR PRC-C3G 2016-2019R]
- Agence Nationale de la Recherche (ANR) [ANR-15-CE15-0001] Funding Source: Agence Nationale de la Recherche (ANR)
- Lundbeck Foundation [R155-2015-2666] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0022058] Funding Source: researchfish
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.
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