Human and murine granzyme B exhibit divergent substrate preferences

Sean P Cullen, Colin Adrain, Alexander U Lüthi, Patrick J Duriez, Seamus J Martin

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)435-44
Number of pages10
JournalThe Journal of cell biology
Volume176
Issue number4
DOIs
Publication statusPublished - 12 Feb 2007

Keywords

  • Amino Acid Sequence/physiology
  • Animals
  • Apoptosis/physiology
  • Apoptosis Regulatory Proteins/metabolism
  • BH3 Interacting Domain Death Agonist Protein/metabolism
  • Caspases/metabolism
  • Cell Line
  • Granzymes/chemistry
  • Humans
  • Mice
  • Mitochondria/metabolism
  • Protein Binding/physiology
  • Species Specificity
  • Substrate Specificity
  • T-Lymphocytes, Cytotoxic/enzymology

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