The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125
| Autor: | Erika J. Mancini, Morag C. Martin, Paul Clarke, Lindsey A. Allan |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Threonine MAPK/ERK pathway Molecular Sequence Data Apoptosis Biochemistry chemistry.chemical_compound Humans Amino Acid Sequence Phosphorylation Molecular Biology Anisomycin Caspase Mitogen-Activated Protein Kinase 1 Caspase-9 Sequence Homology Amino Acid biology Cell Biology Caspase 9 Cell biology chemistry Docking (molecular) Mutagenesis Site-Directed biology.protein HeLa Cells Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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