期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 399, 期 1, 页码 41-52出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.03.064
关键词
crystal structure; protein kinase; autoinhibitory helix; active form; autophosphorylation
资金
- The Hormel Foundation
- National Institutes of Health [CA027502, CA077646, CA120388, R37CA08164, ES016548]
- National Center for Research Resources at the National Institutes of Health [RR-15301]
- US Department of Energy, Office of Basic Energy Sciences [DE-AC02-06CH11357]
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 angstrom and 2.5 angstrom 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 alpha L-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 aL-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 alpha L-helix-independent mechanism, suggesting that a diverse mechanism of auto-inhibition and activation might be adopted by members of a closely related protein kinase family. (C) 2010 Elsevier Ltd. All rights reserved.
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