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标题：Structure of autoinhibited Akt1 reveals mechanism of PIP ₃-mediated activation
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作者：Linda Truebestein ; Harald Hornegger ; Dorothea Anrather 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：33
DOI：10.1073/pnas.2101496118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Akt is an essential protein kinase that controls cell growth, survival, and metabolism. Akt is activated by the lipid second messengers PIP 3 and PI(3,4)P 2 and by phosphorylation. However, the relative contributions of lipid binding and phosphorylation to Akt activity in the cell are controversial. Here, we have determined the structure of autoinhibited Akt1, which reveals how the lipid-binding PH domain maintains the kinase domain in an inactive conformation in the absence of PIP 3. Despite stoichiometric phosphorylation, Akt adopts an autoinhibited conformation with low basal activity in the absence of PIP 3. Our work reveals the mechanistic basis of Akt hyperactivation in cancer and overgrowth diseases and unambiguously establishes that Akt depends on lipids for activity in the cell. The protein kinase Akt is one of the primary effectors of growth factor signaling in the cell. Akt responds specifically to the lipid second messengers phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P 3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P 2] via its PH domain, leading to phosphorylation of its activation loop and the hydrophobic motif of its kinase domain, which are critical for activity. We have now determined the crystal structure of Akt1, revealing an autoinhibitory interface between the PH and kinase domains that is often mutated in cancer and overgrowth disorders. This interface persists even after stoichiometric phosphorylation, thereby restricting maximum Akt activity to PI(3,4,5)P 3- or PI(3,4)P 2-containing membranes. Our work helps to resolve the roles of lipids and phosphorylation in the activation of Akt and has wide implications for the spatiotemporal control of Akt and potentially lipid-activated kinase signaling in general.
关键词：enkinase;signaling;lipid;PIP3;Akt