9n20 | pdb_00009n20

Structure of C3d Bound to a Fragment of FHR-2 and S. aureus Efb-C

spinqualitylabelsall models 9n20, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9n20 is a 3 chain structure with sequence from Homo sapiens and Staphylococcus aureus subsp. aureus Mu50. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.3Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CO3_HUMAN Defects in C3 are the cause of complement component 3 deficiency (C3D) [MIM:613779. A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis. [:] Genetic variation in C3 is associated with susceptibility to age-related macular degeneration type 9 (ARMD9) [MIM:611378. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Defects in C3 are a cause of susceptibility to hemolytic uremic syndrome atypical type 5 (AHUS5) [MIM:612925. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype. Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage. Function CO3_HUMAN C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates. Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. Acylation stimulating protein (ASP): adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for GPR77. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of GPR77. Publication Abstract from PubMed The extracellular fibrinogen-binding protein (Efb) is one of nearly a dozen proteins secreted by Staphylococcus aureus to inhibit complement activation or amplification. The C-terminal domain of Efb (Efb-C) forms a high-affinity interaction with the thioester-containing domain of C3b (TED/C3d), thereby blocking formation of the C3 proconvertase complex through an allosteric mechanism. However, further functional consequences of Efb-C binding to C3b remain unexplored. Here, we identified a previously unknown interaction between Efb-C, C3b, and the complement regulatory molecule FHR2 (factor H-related protein 2). Since the FHR2/C3b interaction is centered upon the 2 C-terminal-most domains of FHR2 (FHR2[3-4]) and the TED/C3d domain of C3b, we tested whether Efb-C could influence the FHR2(3-4)/C3d interaction. We observed a significant enhancement of FHR2(3-4)/C3d binding in the presence of Efb-C. We studied the FHR2(3-4)/C3d/Efb-C complex by X-ray crystallography and found that Efb-C forms few direct interactions with FHR2(3-4). Yet, the presence of Efb-C also enhanced binding of FHR2(3-4) and full-length FHR2 to C3b, suggesting that the effect of Efb-C on the FHR2/C3b interaction arises from increased accessibility of the FHR2-binding site. We found that enhanced FHR2 binding did not impact the rate of C3 convertase formation more than Efb-C alone, nor did it impart decay acceleration or cofactor activity. However, we observed potent, synergistic inhibition of complement downstream of C5 activation by Efb-C and FHR2 but not by Efb-C and FHR2(3-4). Our results show that Efb-C binding to C3b exerts additional inhibitory effects on the central complement components beyond blocking formation of the C3 proconvertase alone. The C-terminal domain of Staphylococcus aureus Efb recruits FHR-2 to C3b, synergistically inhibiting the terminal complement pathway.,Duan H, Kortvely E, Mary JL, Hauck SM, Geisbrecht BV J Immunol. 2025 Nov 22:vkaf316. doi: 10.1093/jimmun/vkaf316. PMID:41273729 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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