The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125

Martin, Morag C, Allan, Lindsey A, Mancini, Erika J and Clarke, Paul R (2008) The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. Journal of Biological Chemistry, 283 (7). pp. 3854-3865. ISSN 0021-9258

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Abstract

Caspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr125 by ERK1/2 MAPKs in response to growth factors. Here, we show that phosphorylation of this site is specific for these classical MAPKs and is not strongly induced when JNK and p38α/β MAPKs are activated by anisomycin. By deletion and mutagenic analysis, we identify domains in caspase-9 and ERK2 that mediate their interaction. Binding of ERK2 to caspase-9 and subsequent phosphorylation of caspase-9 requires a basic docking domain (D domain) in the N-terminal prodomain of the caspase. Mutational analysis of ERK2 reveals a 157TTCD160 motif required for recognition of caspase-9 that acts independently of the putative common docking domain. Molecular modeling supports the conclusion that Arg10 in the D domain of caspase-9 interacts with Asp160 in the TTCD motif of ERK2. Differences in the TTCD motif in other MAPK family members could account for the selective recognition of caspase-9 by ERK1/2. This selectivity may be important for the antiapoptotic role of classical MAPKs in contrast to the proapoptotic roles of stress-activated MAPKs. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
Depositing User: Tom Gittoes
Date Deposited: 29 Jan 2015 16:22
Last Modified: 29 Jan 2015 16:22
URI: http://sro.sussex.ac.uk/id/eprint/52556
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