Abstract
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.
Highlights
Phosphoinositide 3-kinases (PI3Ks) are a family of lipidmodifying enzymes that phosphorylate the 3′-OH group of inositol phospholipids and play key roles in physiology ranging from cell growth and metabolism to organismal development
Like other members of the PI3K family[1,4], PI3KC2α contains a PI3K core that consists of a Ras-binding domain (RBD) and an N-terminal C2 domain, as well as helical and kinase domains (KDs)
To determine the X-ray crystal structure of PI3KC2α, we embarked on an iterative process of construct screening and optimization of various forms of PI3KC2α from different species assisted by hydrogen/deuterium exchange–mass spectrometry (HDX–MS) to identify disordered regions
Summary
Phosphoinositide 3-kinases (PI3Ks) are a family of lipidmodifying enzymes that phosphorylate the 3′-OH group of inositol phospholipids and play key roles in physiology ranging from cell growth and metabolism to organismal development. Recent structural studies[7,8] have enabled the development of selective Vps[34] inhibitors that have been instrumental for the analysis and manipulation of class III PI3K function in autophagy and in the regulation of nutrient signaling. Abrogation of PI3KC2α activity in animal models and in humans leads to kidney cyst formation, skeletal abnormalities, neurological symptoms and cataract formation[25]. In addition to these catalytic roles, PI3KC2α is required for genome stability by acting as a scaffold at the mitotic spindle during cell division[26]. The lack of structural information on PI3KC2α and related class II PI3Ks has greatly hampered the development of isoform-selective pharmacological inhibitors for clinical applications. The molecular basis of the scaffolding function of PI3KC2α at the mitotic spindle via its association with the microtubule-binding protein TACC3 at kinetochore fibers to prevent aneuploidy[26] is unknown
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