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2fsm

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{{STRUCTURE_2fsm| PDB=2fsm | SCENE= }}
{{STRUCTURE_2fsm| PDB=2fsm | SCENE= }}
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'''mitogen activated protein kinase p38alpha (D176A+F327S) activating mutant form-B'''
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===mitogen activated protein kinase p38alpha (D176A+F327S) activating mutant form-B===
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==Overview==
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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 p38alpha 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 p38alpha 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 p38alpha 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 p38alpha activation induced by the L16 switch with auto regulatory characteristics.
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(as it appears on PubMed at http://www.pubmed.gov), where 17059827 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17059827}}
==About this Structure==
==About this Structure==
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[[Category: Mitogen activated protein kinase]]
[[Category: Mitogen activated protein kinase]]
[[Category: P38]]
[[Category: P38]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:15:56 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 20:25:59 2008''

Revision as of 17:26, 27 July 2008

Image:2fsm.png

Template:STRUCTURE 2fsm

mitogen activated protein kinase p38alpha (D176A+F327S) activating mutant form-B

Template:ABSTRACT PUBMED 17059827

About this Structure

2FSM is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structures of p38alpha active mutants reveal conformational changes in L16 loop that induce autophosphorylation and activation., Diskin R, Lebendiker M, Engelberg D, Livnah O, J Mol Biol. 2007 Jan 5;365(1):66-76. Epub 2006 Aug 22. PMID:17059827

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