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

Johannes F. Weijman, Abhishek Kumar, Sam A. Jamieson, Chontelle M. King, Tom T. Caradoc-Davies, Elizabeth C Ledgerwood, James M Murphy, Peter D. Mace

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E2096-E2105
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number11
DOIs
Publication statusPublished - 14 Mar 2017
Externally publishedYes

Keywords

  • ASK1
  • MAP Kinase
  • MKK6
  • Scaffolding
  • Signaling

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