期刊
CELL
卷 174, 期 4, 页码 897-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.07.003
关键词
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资金
- NIH [CA74305, CA062924]
- FAMRI Foundation
- DOE Office of Science [DE-AC02-06CH11357]
- NIGMS [P41GM111244]
- US Department of Energy [DOE KP1605010]
- [DE-SC0012704 (KC0401040)]
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 fnr understanding how Akt is controlled in cell signaling and suggest distinct functions for differentially modified Akt forms.
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