Structure of complement fragment C3b–factor H and implications for host protection by complement regulators

Wu, Jiawang; Wu, Yanze; Ricklin, Daniel; Janssen, B.J.C.; Lambris, John D.; Gros, Piet

doi:10.1038/ni.1755

Cited by 289 publications

(448 citation statements)

References 51 publications

(96 reference statements)

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“…7A, 7B). This conclusion is consistent with the cocrystal structure of C3b-factor H (1-4) wherein residues of factor H equivalent to Glu 108 , Glu 120 , and Glu 144 are fully exposed to the solvent (42). However there exists a caveat.…”

Section: Discussionsupporting

confidence: 77%

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Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

Yadav

Pyaram

Ahmad

et al. 2012

The Journal of Immunology

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Variola and vaccinia viruses, the two most important members of the family Poxviridae, are known to encode homologs of the human complement regulators named smallpox inhibitor of complement enzymes (SPICE) and vaccinia virus complement control protein (VCP), respectively, to subvert the host complement system. Intriguingly, consistent with the host tropism of these viruses, SPICE has been shown to be more human complement-specific than VCP, and in this study we show that VCP is more bovine complement-specific than SPICE. Based on mutagenesis and mechanistic studies, we suggest that the major determinant for the switch in species selectivity of SPICE and VCP is the presence of oppositely charged residues in the central complement control modules, which help enhance their interaction with factor I and C3b, the proteolytically cleaved form of C3. Thus, our results provide a molecular basis for the species selectivity in poxviral complement regulators.

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Section: Discussionsupporting

confidence: 77%

“…5A, 5B). According to a recent model (42), binding of a regulator (VCP or SPICE) to C3b provides a contact interface for initial docking of protease factor I to the C3b/regulator complex. This then results in the formation of a ternary C3b/regulator/factor I complex, leading to cleavages and inactivation of C3b.…”

Section: Discussionmentioning

confidence: 99%

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

Yadav

Pyaram

Ahmad

et al. 2012

The Journal of Immunology

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“…Thus, complex formation with the regulator can only occur if the TED-CUB domain pair is in the closed conformation seen in low salt. The Arg 102 -Glu 1032 salt bridge in C3b and the Arg 104 -Glu 1032 salt bridge in C4b help to stabilise this complex [42,43]. The importance of the domains in the modelling fits.…”

Section: Discussionmentioning

confidence: 97%

“…Crystallographic studies have clarified how five complement regulators bind to active C3b. These C3b complexes include as ligands Factor H short complement regulator domains (SCR) 1/4, membrane cofactor protein (MCP) SCR-3/4, complement receptor type 1 SCR-15/17, decay acceleration factor SCR-2/4 and variola virus SPICE SCR-1/4 [42,43]. All five crystal structures showed that the complexes between C3b and its SCR regulator involve contacts between the MG2 domain in C3b and the first SCR domain of the SCR pair, together with contacts between TED and the second SCR domain of the pair ( Figure 10E).…”

Section: Discussionmentioning

confidence: 99%

Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

Fung

Wright

Gor

et al. 2016

Biochemical Journal

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During the activation of complement C4 to C4b, the exposure of its thioester domain (TED) is crucial for the attachment of C4b to activator surfaces. In the C4b crystal structure, TED forms an Arg 104 -Glu 1032 salt bridge to tether its neighbouring macroglobulin (MG1) domain. Here, we examined the C4b domain structure to test whether this salt bridge affects its conformation. Dual polarisation interferometry of C4b immobilised at a sensor surface showed that the maximum thickness of C4b increased by 0.46 nm with an increase in NaCl concentration from 50 to 175 mM NaCl. Analytical ultracentrifugation showed that the sedimentation coefficient s 20,w of monomeric C4b of 8.41 S in 50 mM NaCl buffer decreased to 7.98 S in 137 mM NaCl buffer, indicating that C4b became more extended. Small angle X-ray scattering reported similar R G values of 4.89-4.90 nm for C4b in 137-250 mM NaCl. Atomistic scattering modelling of the C4b conformation showed that TED and the MG1 domain were separated by 4.7 nm in 137-250 mM NaCl and this is greater than that of 4.0 nm in the C4b crystal structure. Our data reveal that in low NaCl concentrations, both at surfaces and in solution, C4b forms compact TED-MG1 structures. In solution, physiologically relevant NaCl concentrations lead to the separation of the TED and MG1 domain, making C4b less capable of binding to its complement regulators. These conformational changes are similar to those seen previously for complement C3b, confirming the importance of this salt bridge for regulating both C4b and C3b.

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“…Also, the SCR 4 of CFH forms a bridge between TED and the core of C3b (precisely MG1), providing a platform for CFI cofactor activity and, possibly supporting the position of TED while connecting CUB domain undergoes further cleavage. The decay acceleration activity of CFH is due to dislocation of Bb protease, occurring as a result of binding between the first two N-terminal SCR of FH and the α'NT, MG2 and MG6-7 domains of C3b [30,33]. The C-terminal end binds to C3b TED domain and polyanions (glycosaminoglycans, GAG) on the cell surfaces [29].…”

Section: The Alternative Pathway Regulating Proteinsmentioning

confidence: 99%

The role of the alternative pathway of complement activation in glomerular diseases

2018

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The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called 'thick-over.' A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.

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Structure of complement fragment C3b–factor H and implications for host protection by complement regulators

Cited by 289 publications

References 51 publications

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

Species Selectivity in Poxviral Complement Regulators Is Dictated by the Charge Reversal in the Central Complement Control Protein Modules

Domain structure of human complement C4b extends with increasing NaCl concentration: implications for its regulatory mechanism

The role of the alternative pathway of complement activation in glomerular diseases

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