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Published 20 November 2006. doi:10.1083/jcb.200606073
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 619-630
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Article

 The major human and mouse granzymes are structurally and functionally divergent

Dion Kaiserman1, Catherina H. Bird1, Jiuru Sun1, Antony Matthews1, Kheng Ung1, James C. Whisstock1,2, Philip E. Thompson3, Joseph A. Trapani4, and Phillip I. Bird1

1 Department of Biochemistry and Molecular Biology and 2 Victorian Bioinformatics Consortium, Monash University, Victoria 3800, Australia
3 Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville 3052, Australia
4 Peter MacCallum Cancer Institute, Melbourne 8006, Australia

Correspondence to Phillip I. Bird: phil.bird{at}med.monash.edu.au

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.

D. Kaiserman and C.H. Bird contributed equally to this paper.

Abbreviations used in this paper: CL, cytotoxic lymphocyte; IAP, inhibitor of apoptosis protein; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; RCL, reactive center loop; SLO, streptolysin O; wt, wild-type.


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