Molecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation
| Autor: | Peter Cron, Jing Yang, Valerie M. Good, Brian A. Hemmings, David Barford, Daniel Hess, Vivienne Thompson |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Amino Acid Motifs Molecular Sequence Data Protein Serine-Threonine Kinases Mitogen-activated protein kinase kinase Crystallography X-Ray MAP2K7 Proto-Oncogene Proteins Amino Acid Sequence Phosphorylation Molecular Biology Protein kinase B Binding Sites MAP kinase kinase kinase biology Akt/PKB signaling pathway Cyclin-dependent kinase 2 Cell Biology Cyclic AMP-Dependent Protein Kinases Protein Structure Tertiary Cell biology Mutagenesis Site-Directed biology.protein Cyclin-dependent kinase 9 Peptides Proto-Oncogene Proteins c-akt Sequence Alignment |
| Zdroj: | Molecular Cell. 9:1227-1240 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/s1097-2765(02)00550-6 |
| Popis: | Protein kinase B/Akt plays crucial roles in promoting cell survival and mediating insulin responses. The enzyme is stimulated by phosphorylation at two regulatory sites: Thr 309 of the activation segment and Ser 474 of the hydrophobic motif, a conserved feature of many AGC kinases. Analysis of the crystal structures of the unphosphorylated and Thr 309 phosphorylated states of the PKB kinase domain provides a molecular explanation for regulation by Ser 474 phosphorylation. Activation by Ser 474 phosphorylation occurs via a disorder to order transition of the alphaC helix with concomitant restructuring of the activation segment and reconfiguration of the kinase bilobal structure. These conformational changes are mediated by a phosphorylation-promoted interaction of the hydrophobic motif with a channel on the N-terminal lobe induced by the ordered alphaC helix and are mimicked by peptides corresponding to the hydrophobic motif of PKB and potently by the hydrophobic motif of PRK2. |
| Databáze: | OpenAIRE |
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