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Structure paper

TitleStructural basis of phosphatidylinositol 3-kinase C2α function.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 3, Page 218-228, Year 2022
Publish dateMar 7, 2022
AuthorsWen-Ting Lo / Yingyi Zhang / Oscar Vadas / Yvette Roske / Federico Gulluni / Maria Chiara De Santis / Andreja Vujicic Zagar / Heike Stephanowitz / Emilio Hirsch / Fan Liu / Oliver Daumke / Misha Kudryashev / Volker Haucke /
PubMed AbstractPhosphatidylinositol 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, ...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.
External linksNat Struct Mol Biol / PubMed:35256802 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.42 - 4.4 Å
Structure data

EMDB-12191:
Cryo-EM structure of the Phosphatidylinositol 3-kinase type 2a (PI3KC2a) of the class II PI3K family
Method: EM (single particle) / Resolution: 4.4 Å

PDB-7bi2:
PI3KC2aDeltaN and DeltaC-C2
Method: X-RAY DIFFRACTION / Resolution: 3.25 Å

PDB-7bi4:
PI3KC2a core apo
Method: X-RAY DIFFRACTION / Resolution: 2.42 Å

PDB-7bi6:
PI3KC2a core in complex with ATP
Method: X-RAY DIFFRACTION / Resolution: 2.75 Å

PDB-7bi9:
PI3KC2a core in complex with PIK90
Method: X-RAY DIFFRACTION / Resolution: 2.65 Å

Chemicals

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-17G:
9-(6-aminopyridin-3-yl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2(1H)-one

ChemComp-IOD:
IODIDE ION

ChemComp-HOH:
WATER

ChemComp-SO4:
SULFATE ION

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-090:
N-(2,3-DIHYDRO-7,8-DIMETHOXYIMIDAZO[1,2-C] QUINAZOLIN-5-YL)NICOTINAMIDE

Source
  • mus musculus (house mouse)
KeywordsTRANSFERASE / PI3KC2 alpha / kinase

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