The structural basis for complement inhibition by gigastasin, a protease inhibitor from the giant Amazon leech

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.

Wijeyewickrema, Lakshmi C.La Trobe University (author)
Hor, LilianLa Trobe University (author)
Tan, SheareenMonash University (author)
Lameignere, EmilieUniversity of British Columbia (author)
Conway, Edward M.University of British Columbia (author)
Blom, Anna M.Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups(Swepub:lu)klke-abl (author)
Mohlin, Frida C.Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups(Swepub:lu)med-fbr (author)
Liu, XuyuUniversity of Sydney (author)
Payne, Richard J.University of Sydney (author)
Whisstock, James C.Monash University (author)
Pike, Robert N.La Trobe University (author)
Monash UniversityLa Trobe University (creator_code:org_t)

In:Journal of Immunology: The American Association of Immunologists199:11, s. 3883-38910022-17671550-6606

By the author/editor: Pang, Siew Siew; Wijeyewickrema, ...; Hor, Lilian; Tan, Sheareen; Lameignere, Emil ...; Conway, Edward M ...; show more...; Blom, Anna M.; Mohlin, Frida C.; Liu, Xuyu; Payne, Richard J ...; Whisstock, James ...; Pike, Robert N.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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