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  Structural basis of phosphatidylinositol 3-kinase C2α function

Lo, W.-T., Zhang, Y., Vadas, O., Roske, Y., Gulluni, F., De Santis, M. C., et al. (2022). Structural basis of phosphatidylinositol 3-kinase C2α function. Nature Structural and Molecular Biology, 29(3), 218-228. doi:10.1038/s41594-022-00730-w.

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 Creators:
Lo, Wen-Ting1, Author
Zhang, Yingyi2, 3, Author           
Vadas, Oscar4, Author
Roske, Yvette5, Author
Gulluni, Federico6, Author
De Santis, Maria Chiara6, Author
Zagar, Andreja Vujicic7, Author
Stephanowitz, Heike1, Author
Hirsch, Emilio6, Author
Liu, Fan1, Author
Daumke, Oliver5, Author
Kudryashev, Misha2, 3, Author           
Haucke, Volker1, 8, Author
Affiliations:
1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany, ou_persistent22              
2Sofja Kovalevskaja Group, Max Planck Institute of Biophysics, Max Planck Society, ou_2253651              
3Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany, ou_persistent22              
4University of Geneva, Faculty of Medicine, Geneva, Switzerland, ou_persistent22              
5Max Delbrück Centre for Molecular Medicine (MDC), Crystallography, Berlin, Germany, ou_persistent22              
6Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy, ou_persistent22              
7University of Geneva, Section of Pharmacy, Geneva, Switzerland, ou_persistent22              
8Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2021-07-132022-01-212022-03-072022-03
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41594-022-00730-w
BibTex Citekey: lo_structural_2022
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Title: Nature Structural and Molecular Biology
  Other : Nature Struct Biol
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Group
Pages: - Volume / Issue: 29 (3) Sequence Number: - Start / End Page: 218 - 228 Identifier: ISSN: 1545-9993
CoNE: https://pure.mpg.de/cone/journals/resource/954925603763