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

Johannes F WeijmanAbhishek KumarSam A JamiesonChontelle M KingTom T Caradoc-DaviesElizabeth C LedgerwoodJames M MurphyPeter D Mace
Published in: Proceedings of the National Academy of Sciences of the United States of America (2017)
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.
Keyphrases
  • protein kinase
  • transcription factor
  • tyrosine kinase
  • reactive oxygen species
  • oxidative stress
  • cell death
  • structural basis
  • stress induced
  • heat stress
  • amino acid