The Structural Basis for Complement Inhibition by Gigastasin, a Protease Inhibitor from the Giant Amazon Leech
| Autor: | Emilie Lameignere, Sheareen Tan, Edward M. Conway, Anna M. Blom, James C. Whisstock, Lilian Hor, Robert N. Pike, Xuyu Liu, Frida C. Mohlin, Lakshmi C. Wijeyewickrema, Siew Siew Pang, Richard J. Payne |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Serine Proteinase Inhibitors Immunology Biology 03 medical and health sciences Classical complement pathway Complement C1 Catalytic Domain Leeches medicine Immunology and Allergy Animals Humans Complement Pathway Classical Complement Activation Cells Cultured Mannan-binding lectin Complement component 2 Complement Pathway Mannose-Binding Lectin Protease inhibitor (biology) Recombinant Proteins Complement system 030104 developmental biology Complement Inactivating Agents Biochemistry Lectin pathway Factor H Mannose-Binding Protein-Associated Serine Proteases Endothelium Vascular Complement membrane attack complex Peptides medicine.drug |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 199(11) |
| ISSN: | 1550-6606 |
| Popis: | Complement is crucial to the immune response, but dysregulation of the system causes inflammatory disease. Complement is activated by three pathways: classical, lectin, and alternative. The classical and lectin pathways are initiated by the C1r/C1s (classical) and MASP-1/MASP-2 (lectin) proteases. Given the role of complement in disease, there is a requirement for inhibitors to control the initiating proteases. In this article, we show that a novel inhibitor, gigastasin, from the giant Amazon leech, potently inhibits C1s and MASP-2, whereas it is also a good inhibitor of MASP-1. Gigastasin is a poor inhibitor of C1r. The inhibitor blocks the active sites of C1s and MASP-2, as well as the anion-binding exosites of the enzymes via sulfotyrosine residues. Complement deposition assays revealed that gigastasin is an effective inhibitor of complement activation in vivo, especially for activation via the lectin pathway. These data suggest that the cumulative effects of inhibiting both MASP-2 and MASP-1 have a greater effect on the lectin pathway than the more potent inhibition of only C1s of the classical pathway. |
| Databáze: | OpenAIRE |
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