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Structural basis for properdin oligomerization and convertase stimulation in the human complement system

DOI: 10.3389/fimmu.2019.02007 DOI Help

Authors: Dennis V. Pedersen (Aarhus University) , Trine A. F. Gadeberg (Aarhus University) , Caroline Thomas (CHU Nantes) , Yong Wang (University of Copenhagen) , Nicolas Joram (CHU Nantes) , Rasmus K. Jensen (Aarhus University) , Sofia M. M. Mazarakis (Aarhus University) , Margot Revel (INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot) , Carine El Sissy (Hôpital Européen Georges Pompidou) , Steen V. Petersen (Aarhus University) , Kresten Lindorff-Larsen (University of Copenhagen) , Steffen Thiel (Aarhus University) , Nick S. Laursen (Aarhus University) , Véronique Fremeaux-Bacchi (Hôpital Européen Georges Pompidou) , Gregers R. Andersen (Aarhus University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Frontiers In Immunology , VOL 10

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 13062

Open Access Open Access

Abstract: Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.

Journal Keywords: complement; convertase; properdin; complement component C3; crystal structure; regulation; factor B

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

Other Facilities: MAX IV; Petra III

Added On: 03/12/2019 14:13

Documents:
fimmu-10-02007.pdf

Discipline Tags:

Life Sciences & Biotech Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)