The cytotoxic lymphocyte protease granzyme B (GzmB) can promote apoptosis through direct processing and activation of members of the caspase family. GzmB can also cleave the BH3-only protein, BID, to promote caspase-independent mitochondrial permeabilization. Although human and mouse forms of GzmB exhibit extensive homology, these proteases diverge at residues predicted to influence substrate binding. We show that human and mouse GzmB exhibit radical differences in their ability to cleave BID, as well as several other key substrates, such as ICAD and caspase-8. Moreover, pharmacological inhibition of caspases clonogenically rescued human and mouse target cells from apoptosis initiated by mouse GzmB, but failed to do so in response to human GzmB. These data demonstrate that human and murine GzmB are distinct enzymes with different substrate preferences. Our observations also illustrate how subtle differences in enzyme structure can radically affect substrate selection.
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12 February 2007
Article|
February 05 2007
Human and murine granzyme B exhibit divergent substrate preferences
Sean P. Cullen,
Sean P. Cullen
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
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Colin Adrain,
Colin Adrain
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
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Alexander U. Lüthi,
Alexander U. Lüthi
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
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Patrick J. Duriez,
Patrick J. Duriez
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
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Seamus J. Martin
Seamus J. Martin
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
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Sean P. Cullen
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
Colin Adrain
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
Alexander U. Lüthi
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
Patrick J. Duriez
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
Seamus J. Martin
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
Correspondence to Seamus J. Martin: [email protected]
Abbreviations used in this paper: CTL, cytotoxic T lymphocyte; GzmB, granzyme B; NK, natural killer; PI, propidium iodide; SLO, streptolysin O.
Received:
December 05 2006
Accepted:
January 06 2007
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2007
J Cell Biol (2007) 176 (4): 435–444.
Article history
Received:
December 05 2006
Accepted:
January 06 2007
Citation
Sean P. Cullen, Colin Adrain, Alexander U. Lüthi, Patrick J. Duriez, Seamus J. Martin; Human and murine granzyme B exhibit divergent substrate preferences . J Cell Biol 12 February 2007; 176 (4): 435–444. doi: https://doi.org/10.1083/jcb.200612025
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