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

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.

Source: EMBO Journal - April 13, 2017 Category: Molecular Biology Authors: Pedersen, D. V., Roumenina, L., Jensen, R. K., Gadeberg, T. A., Marinozzi, C., Picard, C., Rybkine, T., Thiel, S., Sorensen, U. B., Stover, C., Fremeaux-Bacchi, V., Andersen, G. R. Tags: Immunology, Structural Biology Articles Source Type: research