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Overlapping cleavage motif selectivity of caspases: implications for analysis of apoptotic pathways

MCSTAY, Gavin, Salvesen, G S and Green, D (2008) Overlapping cleavage motif selectivity of caspases: implications for analysis of apoptotic pathways. Cell Death & Differentiation, 15 (2). pp. 322-331. ISSN 1350-9047

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Abstract or description

Caspases orchestrate the controlled demise of a cell after an apoptotic signal
through specific protease activity and cleavage of many substrates altering
protein function and ensuring apoptosis proceeds efficiently. Comparing a variety
of substrates of each apoptotic caspase (2, 3, 6, 7, 8, 9 and 10) showed that the
cleavage sites had a general motif, sometimes specific for one caspase, but other
times specific for several caspases. Using commercially available short
peptide-based substrates and inhibitors the promiscuity for different cleavage
motifs was indicated, with caspase-3 able to cleave most substrates more
efficiently than those caspases to which the substrates are reportedly specific.
In a cell-free system, immunodepletion of caspases before or after cytochrome
c-dependent activation of the apoptosome indicated that the majority of activity
on synthetic substrates was dependent on caspase-3, with minor roles played by
caspases-6 and -7. Putative inhibitors of individual caspases were able to
abolish all cytochrome c-induced caspase activity in a cell-free system and
inhibit apoptosis in whole cells through the extrinsic and intrinsic pathways,
raising issues regarding the use of such inhibitors to define relevant caspases
and pathways. Finally, caspase activity in cells lacking caspase-9 displayed
substrate cleavage activity of a putative caspase-9-specific substrate
underlining the lack of selectivity of peptide-based substrates and inhibitors of
caspases.

Item Type: Article
Faculty: School of Life Sciences and Education > Biological Sciences
Depositing User: Gavin MCSTAY
Date Deposited: 20 Mar 2019 10:33
Last Modified: 20 Mar 2019 10:33
URI: http://eprints.staffs.ac.uk/id/eprint/5474

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