Article

The crystal structure of the active form of the C-terminal kinase domain of mitogen- and stress-activated protein kinase 1.

The Hormel Institute University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
Journal of Molecular Biology (impact factor: 4). 04/2010; 399(1):41-52. DOI:10.1016/j.jmb.2010.03.064 pp.41-52
Source: PubMed

ABSTRACT Mitogen- and stress-activated protein kinase 1 (MSK1) is a growth-factor-stimulated serine/threonine kinase that is involved in gene transcription regulation and proinflammatory cytokine stimulation. MSK1 is a dual kinase possessing two nonidentical protein kinase domains in one polypeptide. We present the active conformation of the crystal structures of its C-terminal kinase domain in apo form and in complex with a nonhydrolyzable ATP analogue at 2.0 A and 2.5 A resolutions, respectively. Structural analysis revealed substantial differences in the contacts formed by the C-terminal helix, which is responsible for the inactivity of other autoinhibited kinases. In the C-terminal kinase domain of MSK1, the C-terminal alphaL-helix is located in the surface groove, but forms no hydrogen bonds with the substrate-binding loop or nearby helices, and does not interfere with the protein's autophosphorylation activity. Mutational analysis confirmed that the alphaL-helix is inherently nonautoinhibitory. Overexpression of the single C-terminal kinase domain in JB6 cells resulted in tumor-promoter-induced neoplastic transformation in a manner similar to that induced by the full-length MSK1 protein. The overall results suggest that the C-terminal kinase domain of MSK1 is regulated by a novel alphaL-helix-independent mechanism, suggesting that a diverse mechanism of autoinhibition and activation might be adopted by members of a closely related protein kinase family.

0 0
 · 
0 Bookmarks
 · 
32 Views
  • Source
    Article: The kinase MSK1 is required for induction of c-fos by lysophosphatidic acid in mouse embryonic stem cells.
    Sebastian Schuck, Ana Soloaga, Gerhard Schratt, J Simon C Arthur, Alfred Nordheim
    [show abstract] [hide abstract]
    ABSTRACT: The regulation of the immediate-early gene c-fos serves as a paradigm for signal-activated gene induction. Lysophosphatidic acid is a potent serum-borne mitogen able to induce c-fos. Analysing the signalling events following stimulation of mouse embryonic stem cells with serum and lysophosphatidic acid, we show that the extracellular signal-regulated kinase (ERK) pathway is involved in mediating c-fos induction. We demonstrate that the ERK-activated kinase MSK1 is required for full c-fos promoter activation, as well as for the phosphorylation of cAMP-responsive element (CRE) binding proteins. We propose that MSK1 contributes to ERK-mediated c-fos promoter activation by targeting CRE binding proteins. These results show that MSK1 is an important ERK-activated mediator of mitogen-stimulated c-fos induction. In addition, they indicate that MSK1 could act through CRE binding proteins to achieve c-fos promoter activation. Thus, they further our understanding of the complex regulation of the model immediate-early gene c-fos.
    BMC Molecular Biology 06/2003; 4:6. · 2.86 Impact Factor
  • Source
    Article: ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions.
    Philippe P Roux, John Blenis
    [show abstract] [hide abstract]
    ABSTRACT: Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.
    Microbiology and Molecular Biology Reviews 07/2004; 68(2):320-44. · 13.02 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

active conformation
 
apo form
 
autoinhibited kinases
 
C-terminal kinase domain
 
crystal structures
 
dual kinase
 
forms
 
full-length MSK1 protein
 
gene transcription regulation
 
growth-factor-stimulated serine/threonine kinase
 
nonidentical protein kinase domains
 
novel alphaL-helix-independent mechanism
 
proinflammatory cytokine stimulation
 
protein's autophosphorylation activity
 
related protein kinase family
 
single C-terminal kinase domain
 
stress-activated protein kinase 1
 
Structural analysis
 
substantial differences
 
tumor-promoter-induced neoplastic transformation