title: The major human and mouse granzymes are structurally and functionally divergent.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology and 2Victorian Bioinformatics Consortium, Monash University, Victoria 3800, Australia.
authors.forename: Dion
authors.initials: D
authors.lastname: Kaiserman
authors.forename: Catherina H
authors.initials: CH
authors.lastname: Bird
authors.forename: Jiuru
authors.initials: J
authors.lastname: Sun
authors.forename: Antony
authors.initials: A
authors.lastname: Matthews
authors.forename: Kheng
authors.initials: K
authors.lastname: Ung
authors.forename: James C
authors.initials: JC
authors.lastname: Whisstock
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Phillip I
authors.initials: PI
authors.lastname: Bird
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D016923:Cell Death; D017124:Conserved Sequence; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D014644:Genetic Variation; D005998:Glycine / Q000378:metabolism; D053804:Granzymes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015843:Serpins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D008562:Membrane Glycoproteins; D019151:Peptide Library; D010455:Peptides; D052899:Pore Forming Cytotoxic Proteins; D015843:Serpins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; C509212:GZMA protein, human; D005998:Glycine