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A C3 specific nanobody that blocks all three activation pathways in the human and murine complement system
- Source :
- Pedersen, H, Jensen, R K, Hansen, A G, Gadeberg, T A F, Thiel, S, Laursen, N S & Andersen, G 2020, ' A C3 specific nanobody that blocks all three activation pathways in the human and murine complement system ', The Journal of Biological Chemistry, vol. 295, no. 26, pp. 8746-8758 . https://doi.org/10.1074/jbc.RA119.012339, J Biol Chem
- Publication Year :
- 2020
-
Abstract
- The complement system is a tightly controlled proteolytic cascade in the innate immune system, which tags intruding pathogens and dying host cells for clearance. An essential protein in this process is complement component C3. Uncontrolled complement activation has been implicated in several human diseases and disorders and has spurred the development of therapeutic approaches that modulate the complement system. Here, using purified proteins and several biochemical assays and surface plasmon resonance, we report that our nanobody, hC3Nb2, inhibits C3 deposition by all complement pathways. We observe that the hC3Nb2 nanobody binds human native C3 and its degradation products with low nanomolar affinity and does not interfere with the endogenous regulation of C3b deposition mediated by Factors H and I. Using negative-stain EM analysis and functional assays, we demonstrate that hC3Nb2 inhibits the substrate-convertase interaction by binding to the MG3 and MG4 domains of C3 and C3b. Furthermore, we notice that hC3Nb2 is cross-reactive and inhibits the lectin and alternative pathway in murine serum. We conclude that hC3Nb2 is a potent, general, and versatile inhibitor of the human and murine complement cascades. Its cross-reactivity suggests that this nanobody may be valuable for analysis of complement activation within animal models of both acute and chronic diseases.
- Subjects :
- 0301 basic medicine
Models, Molecular
Immunology
Complement C3-C5 Convertases
Biochemistry
Hemolysis
03 medical and health sciences
Mice
Animals
Humans
Molecular Biology
Complement Activation
Innate immune system
Sheep
030102 biochemistry & molecular biology
biology
Chemistry
Cell Biology
Complement C3
Single-Domain Antibodies
C3-convertase
Cell biology
Complement system
Complement (complexity)
030104 developmental biology
Single-domain antibody
Structural biology
biology.protein
Alternative complement pathway
Antibody
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Pedersen, H, Jensen, R K, Hansen, A G, Gadeberg, T A F, Thiel, S, Laursen, N S & Andersen, G 2020, ' A C3 specific nanobody that blocks all three activation pathways in the human and murine complement system ', The Journal of Biological Chemistry, vol. 295, no. 26, pp. 8746-8758 . https://doi.org/10.1074/jbc.RA119.012339, J Biol Chem
- Accession number :
- edsair.doi.dedup.....0f54786dd4898b664d8371cf74aaa169