Lo Wen-Ting, Zhang Yingyi, Vadas Oscar, Roske Yvette, Gulluni Federico, De Santis Maria Chiara, Zagar Andreja Vujicic, Stephanowitz Heike, Hirsch Emilio, Liu Fan, Daumke Oliver, Kudryashev Misha, Haucke Volker
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
Max Planck Institute for Biophysics, Frankfurt am Main, Germany.
Nat Struct Mol Biol. 2022 Mar;29(3):218-228. doi: 10.1038/s41594-022-00730-w. Epub 2022 Mar 7.
Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.
2型α磷脂酰肌醇3激酶（PI3KC2α）是结构尚未明确的II类PI3K家族的重要成员，在脂质信号传导、内吞作用、血管生成、病毒复制、血小板形成以及有丝分裂中发挥关键作用。目前对PI3KC2α这些活性的分子基础了解甚少。在此，我们报告了PI3KC2α处于活性和非活性构象时的高分辨率晶体结构以及4.4埃低温电子显微镜（cryo-EM）结构。我们揭示了膜上脂质诱导的PI3KC2α激活的协同机制，该机制涉及其Ras结合和脂质结合的远端Phox同源结构域和C-C2结构域的大规模重新定位，并且可作为整个II类PI3K家族的模型。此外，我们描述了一个PI3KC2α特异性螺旋束结构域，它是其在有丝分裂纺锤体上支架功能的基础。我们的结果增进了我们对PI3K生物学的理解，并为开发具有广泛生物医学应用的II类PI3K功能特异性抑制剂铺平了道路。
