12/29/2022 0 Comments Quickshift orange county robert harris![]() The C3bBb complex is the AP C3 convertase, which catalyzes further C3 cleavage.įigure 1. C3b bound FB is activated by the serine protease factor D (FD) forming the smaller fragment Ba and the larger fragment Bb (60 kDa), which remains non-covalent associated with C3b. C3b can then associate with the zymogen form of factor B (FB) forming the AP C3 proconvertase ( Figure 1A). #QUICKSHIFT ORANGE COUNTY ROBERT HARRIS ACTIVATOR#The point of convergence is the cleavage of the 186 kDa complement component 3 (C3) generating the C3b fragment (178 kDa) which becomes covalently associated with the activator surface. Activation can occur through three pathways known as the classical (CP), the lectin (LP), or the alternative pathway (AP). Activation of the cascade depends on recognition of pathogen-associated molecular patterns or danger-associated molecular patterns on activators such as pathogens and apoptotic host cells. The complement system is furthermore involved in maintenance of host homeostasis ( 1) and is important during neural development ( 2). It is involved in the detection, phagocytosis and killing of invading pathogens, as well as clearance of immune complexes. The complement system is a tightly regulated proteolytic cascade, central to the innate immune system. 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. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. 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. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg 2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. 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. Here we present two crystal structures of FP and two structures of convertase bound FP. 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. 7Department of Biomedicine, Aarhus University, Aarhus, Denmark.6Service d'Immunologie Biologique, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. ![]() ![]()
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