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Granzyme k displays highly restricted substrate specificity that only partially overlaps with granzyme a.

N Bovenschen, R Quadir, AL van den Berg, AB Brenkman, Isabel Vandenberghe UGent, Bart Devreese UGent, J Joore and JA Kummer (2009) Journal of Biological Chemistry. 284(6). p.3504-3512
abstract
Granzymes are serine proteases stored in cytolytic granules of cytotoxic lymphocytes that eliminate virus-infected and tumor cells. Little is known about the molecular mechanism and function of granzyme (Gr) K. GrK is similar to GrA in that they are the only granzymes that display tryptase-like activity. Both granzymes induce cell death by single-stranded nicking of the chromosomal DNA by cleaving the same components of the endoplasmic reticulum-associated SET complex. Therefore, GrK may provide a backup and failsafe mechanism for GrA with redundant specificity. In the present study, we addressed the question of whether GrK displays identical substrate specificity as GrA. In peptide- and protease-proteomic screens, GrK and GrA displayed highly restricted substrate specificities that overlapped only partially. Whereas GrK and GrA cleave SET with similar efficiencies likely at the same sites, both granzymes cleaved the pre-mRNA-binding protein heterogeneous ribonuclear protein K with different kinetics at distinct sites. GrK was markedly more efficient in cleaving heterogeneous ribonuclear protein K than GrA. GrK, but not GrA, cleaved the microtubule network protein beta-tubulin after two distinct Arg residues. Neither GrK cleavage sites in beta-tubulin nor a peptidebased proteomic screen revealed a clear GrK consensus sequence around the P1 residue, suggesting that GrK specificity depends on electrostatic interactions between exosites of the substrate and the enzyme. We hypothesize that GrK not only constitutes a redundant functional backup mechanism that assists GrA-induced cell death but that it also displays a unique function by cleaving its own specific substrates.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
journal title
Journal of Biological Chemistry
J. Biol. Chem.
volume
284
issue
6
pages
3504 - 3512
Web of Science type
Article
Web of Science id
000262872500017
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
5.328 (2009)
JCR rank
48/281 (2009)
JCR quartile
1 (2009)
ISSN
0021-9258
DOI
10.1074/jbc.M806716200
language
English
UGent publication?
yes
classification
A1
id
594784
handle
http://hdl.handle.net/1854/LU-594784
date created
2009-04-16 14:00:13
date last changed
2009-04-22 13:30:24
@article{594784,
  abstract     = {Granzymes are serine proteases stored in cytolytic granules of cytotoxic lymphocytes that eliminate virus-infected and tumor cells. Little is known about the molecular mechanism and function of granzyme (Gr) K. GrK is similar to GrA in that they are the only granzymes that display tryptase-like activity. Both granzymes induce cell death by single-stranded nicking of the chromosomal DNA by cleaving the same components of the endoplasmic reticulum-associated SET complex. Therefore, GrK may provide a backup and failsafe mechanism for GrA with redundant specificity. In the present study, we addressed the question of whether GrK displays identical substrate specificity as GrA. In peptide- and protease-proteomic screens, GrK and GrA displayed highly restricted substrate specificities that overlapped only partially. Whereas GrK and GrA cleave SET with similar efficiencies likely at the same sites, both granzymes cleaved the pre-mRNA-binding protein heterogeneous ribonuclear protein K with different kinetics at distinct sites. GrK was markedly more efficient in cleaving heterogeneous ribonuclear protein K than GrA. GrK, but not GrA, cleaved the microtubule network protein beta-tubulin after two distinct Arg residues. Neither GrK cleavage sites in beta-tubulin nor a peptidebased proteomic screen revealed a clear GrK consensus sequence around the P1 residue, suggesting that GrK specificity depends on electrostatic interactions between exosites of the substrate and the enzyme. We hypothesize that GrK not only constitutes a redundant functional backup mechanism that assists GrA-induced cell death but that it also displays a unique function by cleaving its own specific substrates.},
  author       = {Bovenschen, N and Quadir, R and van den Berg, AL and Brenkman, AB and Vandenberghe, Isabel and Devreese, Bart and Joore, J and Kummer, JA},
  issn         = {0021-9258},
  journal      = {Journal of Biological Chemistry},
  language     = {eng},
  number       = {6},
  pages        = {3504--3512},
  title        = {Granzyme k displays highly restricted substrate specificity that only partially overlaps with granzyme a.},
  url          = {http://dx.doi.org/10.1074/jbc.M806716200},
  volume       = {284},
  year         = {2009},
}

Chicago
Bovenschen, N, R Quadir, AL van den Berg, AB Brenkman, Isabel Vandenberghe, Bart Devreese, J Joore, and JA Kummer. 2009. “Granzyme k Displays Highly Restricted Substrate Specificity That Only Partially Overlaps with Granzyme A.” Journal of Biological Chemistry 284 (6): 3504–3512.
APA
Bovenschen, N., Quadir, R., van den Berg, A., Brenkman, A., Vandenberghe, I., Devreese, B., Joore, J., et al. (2009). Granzyme k displays highly restricted substrate specificity that only partially overlaps with granzyme a. Journal of Biological Chemistry, 284(6), 3504–3512.
Vancouver
1.
Bovenschen N, Quadir R, van den Berg A, Brenkman A, Vandenberghe I, Devreese B, et al. Granzyme k displays highly restricted substrate specificity that only partially overlaps with granzyme a. Journal of Biological Chemistry. 2009;284(6):3504–12.
MLA
Bovenschen, N, R Quadir, AL van den Berg, et al. “Granzyme k Displays Highly Restricted Substrate Specificity That Only Partially Overlaps with Granzyme A.” Journal of Biological Chemistry 284.6 (2009): 3504–3512. Print.