@article{5786319,
  abstract     = {{Granzymes are structurally related serine proteases involved in cell death and immunity. To date four out of five human granzymes have assigned orthologs in mice; however for granzyme H, no murine ortholog has been suggested and its role in cytotoxicity remains controversial. Here, we demonstrate that, as is the case for granzyme C, human granzyme H is an inefficient cytotoxin that together with their similar pattern of GrB divergence and functional similarity strongly hint to their orthologous relationship. Besides analyzing the substrate specificity profile of granzyme H by substrate phage display, substrate cleavage susceptibility of human granzyme H and mouse granzyme C was assessed on a proteome-wide level. The extended specificity profiles of granzymes C and H (i.e. beyond cleavage positions P4-P4') match those previously observed for granzyme B. We demonstrate conservation of these extended specificity profiles among various granzymes as granzyme B cleavage susceptibility of an otherwise granzyme H/C specific cleavage site can simply be conferred by altering the P1-residue to aspartate, the preferred P1-residue of granzyme B. Our results thus indicate a conserved, but hitherto underappreciated specificity-determining role of extended protease-substrate contacts in steering cleavage susceptibility.}},
  author       = {{Plasman, Kim and Maurer-Stroh, Sebastian and Ahmad, Jamshaid and Hao, Han and Kaiserman, Dion and Sirota, Fernanda L and Jonckheere, Veronique and Bird, Philip I and Gevaert, Kris and Van Damme, Petra}},
  issn         = {{1535-9476}},
  journal      = {{MOLECULAR & CELLULAR PROTEOMICS}},
  keywords     = {{TARGET-CELLS,PROTEIN,DIAGONAL CHROMATOGRAPHY,MOUSE GRANZYME,LYMPHOCYTES,PROTEOMICS,APOPTOSIS,DISPLAY,DIVERGENT,EXPRESSION}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{2921--2934}},
  title        = {{Conservation of the extended substrate specificity profiles among homologous granzymes across species}},
  url          = {{http://dx.doi.org/10.1074/mcp.M113.028670}},
  volume       = {{12}},
  year         = {{2013}},
}

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