Akt Kinase Activation Mechanisms Revealed Using Protein Semisynthesis
| Autor: | L. Mario Amzel, Yana Li, Antonieta L. Salguero, Zan Chen, William M. Alexander, Scott B. Ficarro, Daniel R. Dempsey, Albert Z. Liu, Nam Chu, Philip A. Cole, Sandra B. Gabelli, Jarrod A. Marto |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Threonine Protein Conformation Allosteric regulation AKT1 Biology Crystallography X-Ray General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Serine Humans Phosphorylation Protein kinase A Protein kinase B Kinase Pleckstrin Homology Domains HCT116 Cells Cell biology Pleckstrin homology domain Enzyme Activation 030104 developmental biology Protein kinase domain 030220 oncology & carcinogenesis Protein Biosynthesis Protein Processing Post-Translational Proto-Oncogene Proteins c-akt Protein Binding Signal Transduction |
| Zdroj: | Cell. 174(4) |
| ISSN: | 1097-4172 |
| Popis: | Akt is a critical protein kinase that drives cancer proliferation, modulates metabolism, and is activated by C-terminal phosphorylation. The current structural model for Akt activation by C-terminal phosphorylation has centered on intramolecular interactions between the C-terminal tail and the N lobe of the kinase domain. Here, we employ expressed protein ligation to produce site-specifically phosphorylated forms of purified Akt1 that are well suited for mechanistic analysis. Using biochemical, crystallographic, and cellular approaches, we determine that pSer473-Akt activation is driven by an intramolecular interaction between the C-tail and the pleckstrin homology (PH)-kinase domain linker that relieves PH domain-mediated Akt1 autoinhibition. Moreover, dual phosphorylation at Ser477/Thr479 activates Akt1 through a different allosteric mechanism via an apparent activation loop interaction that reduces autoinhibition by the PH domain and weakens PIP3 affinity. These results provide a new framework for understanding how Akt is controlled in cell signaling and suggest distinct functions for differentially modified Akt forms. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|