Structure of and influence of a tick complement inhibitor on human complement component 5

Fredslund, Folmer; Laursen, N.S.; Roversi, Pietro; Jenner, L.; Oliveira, Cristiano L. P.; Pedersen, Jan Skov; Nunn, Miles A.; Lea, Susan M.; DiScipio, Richard G.; Sottrup‐Jensen, Lars; Andersen, Gregers Rom

doi:10.1038/ni.1625

Cited by 122 publications

(150 citation statements)

References 41 publications

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“…This highlights the close relationship between inflammation and coagulation and shows a potent and remarkable effect of upstream inhibition of PRRs. OmCI binds directly to C5 and prevents cleavage by the C5 convertases, thus preventing formation of C5a and TCC (28,38). The attenuating effect on TF is in accordance with previous reports describing C5a-dependent TF expression in both neutrophils and endothelial cells (15,16).…”

Section: Discussionsupporting

confidence: 80%

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Barratt‐Due

Thorgersen

Egge

et al. 2013

The Journal of Immunology

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Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli–induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin–antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.

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Section: Discussionsupporting

confidence: 80%

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Barratt‐Due

Thorgersen

Egge

et al. 2013

The Journal of Immunology

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“…S1B), which at the resolution of 3.6 Å appears to be essentially unchanged relative to the structure of free C5 (21). The interaction of C5 with SSL7 is mediated mainly by the MG1 and MG5 domains with minor contributions from the MG2 and MG6 domains (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…There are now two known binding sites for pathogen proteins inhibiting cleavage of C5. OmCI appears to lock the conformation of C5 and in particular the C345C domain (21), whereas SSL7 binds at the opposite end of the molecule between the distal MG1 and MG5 domains. Both inhibitors appear to block C5 cleavage by interfering with convertase recognition far from C5a.…”

Section: Steric Hindrance and Immune Evasionmentioning

confidence: 99%

Structural basis for inhibition of complement C5 by the SSL7 protein fromStaphylococcus aureus

Laursen

Gordon

Hermans

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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125

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Staphylococcus aureus secretes the SSL7 protein as part of its immune evasion strategy. The protein binds both complement C5 and IgA, yet it is unclear whether SSL7 cross-links these two proteins and, if so, what purpose this serves the pathogen. We have isolated a stable IgA-SSL7-C5 complex, and our crystal structure of the C5-SSL7 complex confirms that binding to C5 occurs exclusively through the C-terminal β-grasp domain of SSL7 leaving the OB domain free to interact with IgA. SSL7 interacts with C5 >70 Å from the C5a cleavage site without inducing significant conformational changes in C5, and efficient inhibition of convertase cleavage of C5 is shown to be IgA dependent. Inhibition of C5a production and bacteriolysis are all shown to require C5 and IgA binding while inhibition of hemolysis is achieved by the C5 binding SSL7 β-grasp domain alone. These results provide a conceptual and structural basis for the development of a highly specific complement inhibitor preventing only the formation of the lytic membrane attack complex without affecting the important signaling functions of C5a. Complement activation triggers cleavage of the three homologous 185-to 200-kDa proteins C3, C4, and C5. Three activation pathways converge on C3 cleavage to C3b (6). Activation by the alternative pathway (AP) results from spontaneous hydrolysis of an internal thioester bond in C3 or by deposition of properdin on an appropriate surface (7), whereas the classical pathway (CP) and lectin-mediated pathways are activated by surface-bound immune complexes or mannan binding lectins/ficolins, respectively. Activation of the CP or the lectin pathway generates the surface-bound C3 convertase (a proteolytic enzyme cleaving C3) C4b2a, whereas the AP generates the C3 convertase C3bBb. Both may recruit an additional C3b molecule to form the CP C5 convertase C4b2a3b or the AP C5 convertase C3bBb3b (8, 9), which cleaves C5 to generate the large fragment C5b and the anaphylatoxin C5a. This binds with high affinity to the C5a receptor (CD88) on myeloid cells triggering G protein (Gα I and Gα 16 )-mediated cell activation, chemotaxis, respiratory burst, and release of proinflammatory mediators (10). C5b quickly associates with C6, C7, C8, and multiple molecules of C9 to form the membrane attack complex (MAC) that results in rapid cell lysis (11). Elevated levels of C5a are implicated in a wide range of inflammatory disorders, such as rheumatoid arthritis, ischemia/reperfusion injury, sepsis, and fibrotic conditions (12). MAC deposition through C5b on erythrocytes results in destruction of these cells in the hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH) (13). In addition, excessive MAC formation is linked with the pathophysiology of conditions such as antibody-mediated transplant rejection (14), inflammatory neuropathies (15) and multiple sclerosis (16).Given its importance to innate immune clearance, pathogens have developed many strategies to prevent complement activation (17). The Staphylococcal Superantigen-Like protein 7 (SSL7)...

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“…In C3b, TED and the MG1 domain make contact with each other through an Arg 102 (MG1)-Glu 1032 (TED) salt bridge ( Figure 1B). In contrast, even though inactive C5 showed the same buried TED-MG8 arrangement seen in C3 and C4 [7], the crystal structure of C5b in its complex with C6 showed that its TED and MG1 domains were separated by up to 5 nm and were not in contact ( Figure 1C) [8]. Protein crystal growth requires non-physiological conditions such as low or high salt concentrations, and these may induce non-native protein conformations within the crystal lattice.…”

Section: Introductionmentioning

confidence: 98%

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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Structure of and influence of a tick complement inhibitor on human complement component 5

Cited by 122 publications

References 41 publications

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis

Structural basis for inhibition of complement C5 by the SSL7 protein fromStaphylococcus aureus

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

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