Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System

Frontiers in Immunology

Margot Revel¹  Kresten Lindorff-Larsen²  Yong Wang²  Steffen Thiel³  Steen V. Petersen³  Dennis V. Pedersen⁴  Gregers R. Andersen⁴  Trine A. F. Gadeberg⁴  Sofia M. M. Mazarakis⁴  Rasmus K. Jensen⁴  Nick S. Laursen⁴  Véronique Fremeaux-Bacchi⁵  Carine El Sissy⁵  Caroline Thomas⁶  Nicolas Joram⁷ 

[1] Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France;Department of Biology, Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, Denmark;Department of Biomedicine, Aarhus University, Aarhus, Denmark;Department of Molecular Biology and Genetics, Center for Structural Biology, Aarhus University, Aarhus, Denmark;Service d'Immunologie Biologique, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France;Service d'Oncologie Pédiatrique, CHU Nantes, Hôpital Mère Enfant, Nantes, France;Service de Réanimation Pédiatrique, CHU Nantes, Nantes, France;

关键词: complement;    convertase;    properdin;    complement component C3;    crystal structure;    regulation;   

DOI  :  10.3389/fimmu.2019.02007

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown