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

Weijman, JF; Kumar, A; Jamieson, SA; King, CM; Caradoc-Davies, TT; Ledgerwood, EC; Murphy, JM; Mace, PD

Author(s): Weijman, JF; Kumar, A; Jamieson, SA; King, CM; Caradoc-Davies, TT; Ledgerwood, EC; Murphy, JM; Mace, PD;
Details: Publication Year 2017-02-27,Volume 114,Issue #11,Page E2096-E2105
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Journal Article
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.
Publisher: NAS
Research Division(s): Cell Signalling And Cell Death
PubMed ID: 28242696
Link To PubMed Central Version: https://www-ncbi-nlm-nih-gov/pmc/articles/PMC5358389/
Publisher's Version: https://doi.org/10.1073/pnas.1620813114
ARC Grants: ARC/1105754,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-04-06 09:27:14

Last Modified: 2018-01-10 10:04:34