Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

Apoptosis signal-regulating kinases (ASK1–3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscur...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2017-03, Vol.114 (11), p.E2096-E2105
Hauptverfasser: Weijman, Johannes F., Kumar, Abhishek, Jamieson, Sam A., King, Chontelle M., Caradoc-Davies, Tom T., Ledgerwood, Elizabeth C., Murphy, James M., Mace, Peter D.
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Sprache:eng
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Zusammenfassung:Apoptosis signal-regulating kinases (ASK1–3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation. The crystal structure of the central regulatory region reveals an unusually compact tetratricopeptide repeat (TPR) region capped by a cryptic pleckstrin homology domain. Biochemical assays show that both a conserved surface on the pleckstrin homology domain and an intact TPR region are required for ASK1 activity. We propose a model in which the central regulatory region promotes ASK1 activity via its pleckstrin homology domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. Such an architecture provides a mechanism for control of ASK-type kinases by diverse activators and inhibitors and demonstrates an unexpected level of autoregulatory scaffolding in mammalian stress-activated MAP kinase signaling.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1620813114