Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ
Nature structural & molecular biology(2024)
摘要
The conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase gamma (PI3K gamma) is critical for neutrophil chemotaxis and cancer metastasis. PI3K gamma is activated by G beta gamma heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3K gamma-human G beta gamma complexes in the presence of substrates/analogs, revealing two G beta gamma binding sites: one on the p110 gamma helical domain and another on the p101 C-terminal domain. Comparison with PI3K gamma alone reveals conformational changes in the kinase domain upon G beta gamma binding that are similar to Ras center dot GTP-induced changes. Assays of variants perturbing the G beta gamma binding sites and interdomain contacts altered by G beta gamma binding suggest that G beta gamma recruits the enzyme to membranes and allosterically regulates activity via both sites. Studies of zebrafish neutrophil migration align with these findings, paving the way for in-depth investigation of G beta gamma-mediated activation mechanisms in this enzyme family and drug development for PI3K gamma. Phosphoinositide 3-kinase gamma plays critical roles in neutrophil chemotaxis and cancer metastasis. Here, using cryo-EM and functional studies, the authors reveal how two molecules of a key activator, G beta gamma, bind to and alter the conformation of the enzyme.
更多查看译文
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要