7BI2

PI3KC2aDeltaN and DeltaC-C2

Summary for 7BI2

• Entry DOI: 10.2210/pdb7bi2/pdb
• Descriptor: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha,Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha, 1,2-ETHANEDIOL, 9-(6-aminopyridin-3-yl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2(1H)-one, ... (5 entities in total)
• Functional Keywords: pi3kc2 alpha, kinase, transferase
• Biological source: Mus musculus (House Mouse); More
• Total number of polymer chains: 1
• Total formula weight: 132490.89

Authors

Lo, W.T.,Roske, Y.,Daumke, O.,Haucke, V. (deposition date: 2021-01-12, release date: 2022-03-09, Last modification date: 2024-01-31)

Primary citation

Lo, W.T.,Zhang, Y.,Vadas, O.,Roske, Y.,Gulluni, F.,De Santis, M.C.,Zagar, A.V.,Stephanowitz, H.,Hirsch, E.,Liu, F.,Daumke, O.,Kudryashev, M.,Haucke, V.
Structural basis of phosphatidylinositol 3-kinase C2 alpha function.
Nat.Struct.Mol.Biol., 29:218-228, 2022

PubMed 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.

PubMed: 35256802
DOI: 10.1038/s41594-022-00730-w

Experimental method

X-RAY DIFFRACTION (3.25 Å)