Abstract

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.

Keywords

PhosphorylationBiologyProtein kinase BKinaseCell biologyProtein kinase domainStructural motifProtein kinase ABiochemistryMutantGene

MeSH Terms

Amino Acid MotifsAmino Acid SequenceBinding SitesCrystallographyX-RayCyclic AMP-Dependent Protein KinasesModelsMolecularMolecular Sequence DataMutagenesisSite-DirectedPeptidesPhosphorylationProtein Serine-Threonine KinasesProtein StructureTertiaryProto-Oncogene ProteinsProto-Oncogene Proteins c-aktSequence Alignment

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Publication Info

Year
2002
Type
article
Volume
9
Issue
6
Pages
1227-1240
Citations
416
Access
Closed

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Cite This

Jing Yang, Peter Cron, Vivienne Thompson et al. (2002). Molecular Mechanism for the Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation. Molecular Cell , 9 (6) , 1227-1240. https://doi.org/10.1016/s1097-2765(02)00550-6

Identifiers

DOI
10.1016/s1097-2765(02)00550-6
PMID
12086620

Data Quality

Data completeness: 86%