5ULM

Structure of the ASK1 central regulatory region

5ULM の概要

• エントリーDOI: 10.2210/pdb5ulm/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase 5, GLYCEROL (3 entities in total)
• 機能のキーワード: ask1, pleckstrin homology, tetratricopeptide, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q99683
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90741.90

構造登録者

Mace, P.D.,Kumar, A.,Caradoc-Davies, T.T. (登録日: 2017-01-24, 公開日: 2017-03-01, 最終更新日: 2024-03-06)

主引用文献

Weijman, J.F.,Kumar, A.,Jamieson, S.A.,King, C.M.,Caradoc-Davies, T.T.,Ledgerwood, E.C.,Murphy, J.M.,Mace, P.D.
Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1.
Proc. Natl. Acad. Sci. U.S.A., 114:E2096-E2105, 2017

PubMed 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.

PubMed: 28242696
DOI: 10.1073/pnas.1620813114

実験手法

X-RAY DIFFRACTION (2.1 Å)