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Nat Struct Mol Biol. 2014 Aug;21(8):704-11. doi: 10.1038/nsmb.2861. Epub 2014 Jul 20.

Allosteric enhancement of MAP kinase p38α's activity and substrate selectivity by docking interactions.

Author information

1
1] Research and Development Department, Japan Biological Informatics Consortium, Tokyo, Japan. [2] Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
2
Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
3
1] Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan. [2] Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.
4
1] Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. [2] Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.

Abstract

Mitogen-activated protein kinases (MAPKs) are essential to intracellular signal transduction. MAPKs anchor their pathway-specific substrates through so-called 'docking interactions' at locations distal from the active site. Docking interactions ensure efficient substrate recognition, but their contribution to the kinase reaction itself remains unclear. Herein, we use solution NMR to analyze the interaction between dually phosphorylated, active human p38α and the C-terminal fragments of its substrate MK2. p38α phosphorylation and ATP loading collaboratively induce the active conformation; subsequently, p38α accommodates MK2 phosphoacceptor residues in its active site. The docking interaction enhances binding of ATP and the phosphoacceptor to p38α, accelerating the phosphotransfer reaction. Thus, the docking interaction enhances p38α's enzymatic activity toward pathway-specific substrates allosterically as well as by the anchor effect. These findings clarify how MAPK cascades are organized in cells, even under ATP-depleted conditions often associated with environmental stress.

PMID:
25038803
DOI:
10.1038/nsmb.2861
[Indexed for MEDLINE]

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