Linked Life Data

15284239

Source:http://linkedlifedata.com/resource/pubmed/id/15284239

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2004-11-1
pubmed:abstractText
Mitogen-activated protein (MAP) kinases compose a family of serine/threonine kinases that function in many signal transduction pathways and affect various cellular phenotypes. Despite the abundance of available data, the exact role of each MAP kinase is not completely defined, in part because of the inability to activate MAP kinase molecules individually and specifically. Based on activating mutations found in the yeast MAP kinase p38/Hog1 (Bell, M., Capone, R., Pashtan, I., Levitzki, A., and Engelberg, D. (2001) J. Biol. Chem. 276, 25351-25358), we designed and constructed single and multiple mutants of human MAP kinase p38alpha. Single (p38D176A, p38F327L, and p38F327S) and subsequent double (p38D176A/F327L and p38D176A/F327S) mutants acquired high intrinsic activity independent of any upstream regulation and reached levels of 10 and 25%, respectively, in reference to the dually phosphorylated wild type p38alpha. The active p38 mutants have retained high specificity toward p38 substrates and were inhibited by the specific p38 inhibitors SB-203580 and PD-169316. We also show that similar mutations can render p38gamma active as well. Based on the available structures of p38 and ERK2, we have analyzed the p38 mutants and identified a hydrophobic core stabilized by three aromatic residues, Tyr-69, Phe-327, and Trp-337, in the vicinity of the L16 loop region. Upon activation, a segment of the L16 loop, including Phe-327, becomes disordered. Structural analysis suggests that the active p38 mutants emulate the conformational changes imposed naturally by dual phosphorylation, namely, destabilization of the hydrophobic core. Essentially, the hydrophobic core is an inherent stabilizer that maintains low basal activity level in unphosphorylated p38.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
47040-9
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15284239-Amino Acid Sequence, pubmed-meshheading:15284239-Blotting, Western, pubmed-meshheading:15284239-Catalysis, pubmed-meshheading:15284239-Cloning, Molecular, pubmed-meshheading:15284239-DNA Primers, pubmed-meshheading:15284239-Dose-Response Relationship, Drug, pubmed-meshheading:15284239-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:15284239-Glutathione Transferase, pubmed-meshheading:15284239-Humans, pubmed-meshheading:15284239-Kinetics, pubmed-meshheading:15284239-MAP Kinase Signaling System, pubmed-meshheading:15284239-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:15284239-Mitogen-Activated Protein Kinase 14, pubmed-meshheading:15284239-Models, Molecular, pubmed-meshheading:15284239-Molecular Sequence Data, pubmed-meshheading:15284239-Mutagenesis, Site-Directed, pubmed-meshheading:15284239-Mutation, pubmed-meshheading:15284239-Phosphorylation, pubmed-meshheading:15284239-Point Mutation, pubmed-meshheading:15284239-Protein Binding, pubmed-meshheading:15284239-Protein Conformation, pubmed-meshheading:15284239-Protein Structure, Secondary, pubmed-meshheading:15284239-Protein Structure, Tertiary, pubmed-meshheading:15284239-Sequence Homology, Amino Acid, pubmed-meshheading:15284239-Threonine, pubmed-meshheading:15284239-p38 Mitogen-Activated Protein Kinases
pubmed:year
2004
pubmed:articleTitle
Active mutants of the human p38alpha mitogen-activated protein kinase.
pubmed:affiliation
Department of Biological Chemistry, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't