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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. LU ; Mohlin, Frida C. LU ; Liu, Xuyu and Payne, Richard J., et al. (2017) In Journal of Immunology 199(11). p.3883-3891
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... (More)

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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published
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Journal of Immunology
volume
199
issue
11
pages
9 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:85034745892
  • wos:000415967800019
ISSN
0022-1767
DOI
10.4049/jimmunol.1700158
language
English
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yes
id
7800f135-c226-4aa9-9690-776ab1f9c57e
date added to LUP
2017-12-07 14:10:49
date last changed
2018-01-16 13:27:06
@article{7800f135-c226-4aa9-9690-776ab1f9c57e,
  abstract     = {<p>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.</p>},
  author       = {Pang, Siew Siew and Wijeyewickrema, Lakshmi C. and Hor, Lilian and Tan, Sheareen and Lameignere, Emilie and Conway, Edward M. and Blom, Anna M. and Mohlin, Frida C. and Liu, Xuyu and Payne, Richard J. and Whisstock, James C. and Pike, Robert N.},
  issn         = {0022-1767},
  language     = {eng},
  month        = {12},
  number       = {11},
  pages        = {3883--3891},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {The structural basis for complement inhibition by gigastasin, a protease inhibitor from the giant Amazon leech},
  url          = {http://dx.doi.org/10.4049/jimmunol.1700158},
  volume       = {199},
  year         = {2017},
}