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Title | Functional and structural insight into properdin control of complement alternative pathway amplification. |
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Journal, issue, pages | EMBO J, Vol. 36, Issue 8, Page 1084-1099, Year 2017 |
Publish date | Apr 13, 2017 |
Authors | Dennis V Pedersen / Lubka Roumenina / Rasmus K Jensen / Trine Af Gadeberg / Chiara Marinozzi / Capucine Picard / Tania Rybkine / Steffen Thiel / Uffe Bs Sørensen / Cordula Stover / Veronique Fremeaux-Bacchi / Gregers R Andersen / |
PubMed 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 ...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 while our monomers enable detailed structural insight paving the way for novel modulators of complement. |
External links | EMBO J / PubMed:28264884 / PubMed Central |
Methods | SAS (X-ray synchrotron) |
Structure data | SASDB59: SASDB69: |
Source |
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