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

Siew Siew Pang, Lakshmi C. Wijeyewickrema, Lilian Hor, Sheareen Tan, Emilie Lameignere, Edward M. Conway, Anna M. Blom, Frida C. Mohlin, Xuyu Liu, Richard J. Payne, James C. Whisstock, Robert N. Pike

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1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3883-3891
Number of pages9
JournalJournal of Immunology
Volume199
Issue number11
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

Pang, Siew Siew ; Wijeyewickrema, Lakshmi C. ; Hor, Lilian ; Tan, Sheareen ; Lameignere, Emilie ; Conway, Edward M. ; Blom, Anna M. ; Mohlin, Frida C. ; Liu, Xuyu ; Payne, Richard J. ; Whisstock, James C. ; Pike, Robert N. / The structural basis for complement inhibition by gigastasin, a protease inhibitor from the giant Amazon leech. In: Journal of Immunology. 2017 ; Vol. 199, No. 11. pp. 3883-3891.
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abstract = "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.",
author = "Pang, {Siew Siew} and Wijeyewickrema, {Lakshmi C.} and Lilian Hor and Sheareen Tan and Emilie Lameignere and Conway, {Edward M.} and Blom, {Anna M.} and Mohlin, {Frida C.} and Xuyu Liu and Payne, {Richard J.} and Whisstock, {James C.} and Pike, {Robert N.}",
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Pang, SS, Wijeyewickrema, LC, Hor, L, Tan, S, Lameignere, E, Conway, EM, Blom, AM, Mohlin, FC, Liu, X, Payne, RJ, Whisstock, JC & Pike, RN 2017, 'The structural basis for complement inhibition by gigastasin, a protease inhibitor from the giant Amazon leech', Journal of Immunology, vol. 199, no. 11, pp. 3883-3891. https://doi.org/10.4049/jimmunol.1700158

The structural basis for complement inhibition by gigastasin, a protease inhibitor from the giant Amazon leech. / Pang, Siew Siew; Wijeyewickrema, Lakshmi C.; Hor, Lilian; Tan, Sheareen; Lameignere, Emilie; Conway, Edward M.; Blom, Anna M.; Mohlin, Frida C.; Liu, Xuyu; Payne, Richard J.; Whisstock, James C.; Pike, Robert N.

In: Journal of Immunology, Vol. 199, No. 11, 01.12.2017, p. 3883-3891.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The structural basis for complement inhibition by gigastasin, a protease inhibitor from the giant Amazon leech

AU - Pang, Siew Siew

AU - Wijeyewickrema, Lakshmi C.

AU - Hor, Lilian

AU - Tan, Sheareen

AU - Lameignere, Emilie

AU - Conway, Edward M.

AU - Blom, Anna M.

AU - Mohlin, Frida C.

AU - Liu, Xuyu

AU - Payne, Richard J.

AU - Whisstock, James C.

AU - Pike, Robert N.

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N2 - 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.

AB - 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.

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DO - 10.4049/jimmunol.1700158

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SP - 3883

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JF - Journal of Immunology

SN - 0022-1767

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