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: 4.33). 04/2010; 399(1):41-52. DOI: 10.1016/j.jmb.2010.03.064
Source: PubMed


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.

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Available from: Igor D'Angelo
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    • "The software programs used for molecular modeling and docking were supplied by LigandFit (Montes et al., 2007) interfaced with Accelrys DiscoveryStudio3.1 (Accelrys Inc., San Diego, CA, USA). The crystal structures of 7 kinases were obtained from the protein data bank; Rho kinase 2 (pdb entry; 2H9V; Yamaguchi et al., 2006) and Rho kinase 1 (pdb entry: 3NCZ; Ginn et al., 2010), mitogen-and stress-activated protein kinase 1 (pdb entry: 3KN5; Malakhova et al., 2010), protein kinase A (pdb entry: 3POO), protein kinase CZ (pdb entry: 3TXO; van Eis et al., 2011), p90 ribosomal S6 kinase 1 (pdb entry: 2WNT), and serum-and glucocorticoid-induced protein kinase (pdb entry: 3HDM; Hammond et al., 2009). The CHARMM force field (Brooks et al., 2009) was used to define the 3D structure and the binding cavities. "
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