Abstract
p38 mitogen-activated protein (MAP) kinases function in numerous signaling processes and are crucial for normal functions of cells and organisms. Abnormal p38 activity is associated with inflammatory diseases and cancers making the understanding of its activation mechanisms highly important. p38s are commonly activated by phosphorylation, catalyzed by MAP kinase kinases (MKKs). Moreover, it was recently revealed that the p38α is also activated via alternative pathways, which are MKK independent. The structural basis of p38 activation, especially in the alternative pathways, is mostly unknown. This lack of structural data hinders the study of p38's biology as well as the development of novel strategies for p38 inhibition. We have recently discovered and optimized a novel set of intrinsically active p38 mutants whose activities are independent of any upstream activation. The high-resolution crystal structures of the intrinsically active p38α mutants reveal that local alterations in the L16 loop region promote kinase activation. The L16 loop can be thus regarded as a molecular switch that upon conformational changes promotes activation. We suggest that similar conformational changes in L16 loop also occur in natural activation mechanisms of p38α in T-cells. Our biochemical studies reveal novel mechanistic insights into the activation process of p38. In this regard, the results indicate that the activation mechanism of the mutants involves dimerization and subsequent trans autophosphorylation on Thr180 (on the phosphorylation lip). Finally, we suggest a model of in vivo p38α activation induced by the L16 switch with auto regulatory characteristics.
Original language | English |
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Pages (from-to) | 66-76 |
Number of pages | 11 |
Journal | Journal of Molecular Biology |
Volume | 365 |
Issue number | 1 |
DOIs | |
State | Published - 5 Jan 2007 |
Bibliographical note
Funding Information:This work was supported by Israeli Science Foundation (ISF) grants 495-03 (to O. L.) and funds from the Altertum Elsa and Elyahu Pen Foundations (to O. L. and D. E.). We thank Mr Nadav Askari for providing p38α Y182F and p38α T180A mutants. We thank the staff of the ESRF, Grenoble, France for their helpful assistance.
Keywords
- active mutants
- crystal structure
- dimerization
- mitogen activated protein kinase
- p38