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The major human and mouse granzymes are structurally and functionally divergent
Open accessAbstract
Approximately 2% of mammalian genes encode proteases. Comparative genomics reveals that those involved in immunity and reproduction show the most interspecies diversity and evidence of positive selection during evolution. This is particularly true of granzymes, the cytotoxic proteases of natural killer cells and CD8+ T cells. There are 5 granzyme genes in humans and 10 in mice, and it is suggested that granzymes evolve to meet species-specific immune challenge through gene duplication and more subtle alterations to substrate specificity. We show that mouse and human granzyme B have distinct structural and functional characteristics. Specifically, mouse granzyme B is 30 times less cytotoxic than human granzyme B and does not require Bid for killing but regains cytotoxicity on engineering of its active site cleft. We also show that mouse granzyme A is considerably more cytotoxic than human granzyme A. These results demonstrate that even “orthologous” granzymes have species-specific functions, having evolved in distinct environments that pose different challenges.
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Cited by
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Del Re, D. P., Amgalan, D., Linkermann, A., Liu, Q., & Kitsis, R. N. (2019) · Physiological Reviews · doi:10.1152/physrev.00022.2018 · Cited by 961
MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets
Kurioka, A., Ussher, J. E., Cosgrove, C., Clough, C., Fergusson, J. R., Smith, K., Kang, Y.-H., Walker, L. J., Hansen, T. H., Willberg, C. B., et al. (2015) · Mucosal Immunology · doi:10.1038/mi.2014.81 · Cited by 398
Granzymes in cancer and immunity
Cullen, S. P., Brunet, M., & Martin, S. J. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.206 · Cited by 391
Serine proteases of the human immune system in health and disease
Heutinck, K. M., ten Berge, I. J. M., Hack, C. E., Hamann, J., & Rowshani, A. T. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.04.020 · Cited by 262
Metadata
- Authors
- Kaiserman, D., Bird, C. H., Sun, J., Matthews, A., Ung, K., Whisstock, J. C., Thompson, P. E., Trapani, J. A., & Bird, P. I.
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2006-11-20
- Volume
- 175
- Issue
- 4
- Pages
- 619-630
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- OpenAlex
- W2023075010
- Cited by
- 197
- References
- 0
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Kaiserman, D., Bird, C. H., Sun, J., Matthews, A., Ung, K., Whisstock, J. C., Thompson, P. E., Trapani, J. A., & Bird, P. I. (2006). The major human and mouse granzymes are structurally and functionally divergent. The Journal of Cell Biology. https://doi.org/10.1083/jcb.200606073
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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