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J Biol Chem, Vol. 274, Issue 43, 30468-30473, October 22, 1999
From the Serine proteases (granzymes) contained within the
cytoplasmic granules of cytotoxic T cells and natural killer cells play a variety of roles including the induction of target cell apoptosis, breakdown of extracellular matrix proteins and induction of cytokine secretion by bystander leukocytes. Different granzymes display proteolytic specificities that mimic the activities of trypsin or
chymotrypsin, or may cleave substrates at acidic ("Asp-ase") or at
long unbranched amino acids such as Met ("Met-ase"). Here, we
report that recombinant granzyme H has chymotrypsin-like (chymase) activity, the first report of a human granzyme with this proteolytic specificity. Recombinant 32-kDa granzyme H expressed in the baculovirus vector pBacPAK8 was secreted from Sf21 cells and recovered by Ni-affinity chromatography, using a poly-His tag encoded at the predicted carboxyl terminus of full-length granzyme H cDNA. The granzyme H efficiently cleaved Suc-Phe-Leu-Phe-SBzl (v = 185 nM/s at [S] = 0.217 mM) and also
hydrolyzed Boc-Ala-Ala-X-SBzl (X = Phe,
Tyr, Met, Nle, or Nva) with slower rates but had little tryptase or
Asp-ase activity. Enzymatic activity was inhibited completely by 0.1 mM 3,4-dichloroisocoumarin and 84% by 1.0 mM
phenylmethylsulfonyl fluoride. Fluoresceinated granzyme H was
internalized in a temperature-dependent manner by
Jurkat cells into endosome-like vesicles, suggesting that it can
bind to cell surface receptors similar to those that bind granzyme B. This suggests a hitherto unsuspected intracellular function for
granzyme H.
The Human Cytotoxic T Cell Granule Serine Protease Granzyme H
Has Chymotrypsin-like (Chymase) Activity and Is Taken Up into
Cytoplasmic Vesicles Reminiscent of Granzyme B-containing
Endosomes
,
The John Connell Laboratory, The Austin
Research Institute, Studley Road, Heidelberg, 3084, Australia and
the § School of Chemistry and Biochemistry, Georgia
Institute of Technology, Atlanta, Georgia 30332-0400
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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