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J Biol Chem. 2014 Aug 22;289(34):23546-56. doi: 10.1074/jbc.M114.578237. Epub 2014 Jul 8.

The p38β mitogen-activated protein kinase possesses an intrinsic autophosphorylation activity, generated by a short region composed of the α-G helix and MAPK insert.

Author information

1
From the Department of Biological Chemistry, Institute of Life Science and.
2
the Faculty of Biology, Smoler Proteomics Center, Technion - Israel Institute of Technology, Haifa 32000, Israel.
3
From the Department of Biological Chemistry, Institute of Life Science and the Wolfson Centre for applied Structural Biology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
4
the Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309, and.
5
From the Department of Biological Chemistry, Institute of Life Science and the CREATE-NUS-HUJ, Cellular & Molecular Mechanisms of Inflammation Program, National University of Singapore, Singapore 138602 engelber@cc.huji.ac.il.

Abstract

Protein kinases are regulated by a large number of mechanisms that vary from one kinase to another. However, a fundamental activation mechanism shared by all protein kinases is phosphorylation of a conserved activation loop threonine residue. This is achieved in many cases via autophosphorylation. The mechanism and structural basis for autophosphorylation are not clear and are in fact enigmatic because this phosphorylation occurs when the kinase is in its inactive conformation. Unlike most protein kinases, MAP kinases are not commonly activated by autophosphorylation but rather by MEK-dependent phosphorylation. Here we show that p38β, a p38 isoform that is almost identical to p38α, is exceptional and spontaneously autoactivates by autophosphorylation. We identified a 13-residue-long region composed of part of the αG-helix and the MAPK insert that triggers the intrinsic autophosphorylation activity of p38β. When inserted into p38α, this fragment renders it spontaneously active in vitro and in mammalian cells. We further found that an interaction between the N terminus and a particular region of the C-terminal extension suppresses the intrinsic autophosphorylation of p38β in mammalian cells. Thus, this study identified the structural motif responsible for the unique autophosphorylation capability of p38β and the motif inhibiting this activity in living cells. It shows that the MAPK insert and C-terminal extension, structural motifs that are unique to MAPKs, play a critical role in controlling autophosphorylation.

KEYWORDS:

Autophosphorylation; Mitogen-activated Protein Kinase (MAPK); Phosphorylation; Signal Transduction; p38; p38 MAPK

PMID:
25006254
PMCID:
PMC4156038
DOI:
10.1074/jbc.M114.578237
[Indexed for MEDLINE]
Free PMC Article

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