Structural basis of phosphatidylinositol 3-kinase C2α function.

Autor: Lo WT; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. lo@fmp-berlin.de., Zhang Y; Max Planck Institute for Biophysics, Frankfurt am Main, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany.; Biological Cryo-EM Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China., Vadas O; University of Geneva, Faculty of Medicine, Geneva, Switzerland., Roske Y; Max Delbrück Centre for Molecular Medicine (MDC), Crystallography, Berlin, Germany., Gulluni F; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., De Santis MC; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., Zagar AV; University of Geneva, Section of Pharmacy, Geneva, Switzerland., Stephanowitz H; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany., Hirsch E; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy., Liu F; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany., Daumke O; Max Delbrück Centre for Molecular Medicine (MDC), Crystallography, Berlin, Germany., Kudryashev M; Max Planck Institute for Biophysics, Frankfurt am Main, Germany.; Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany., Haucke V; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. haucke@fmp-berlin.de.; Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany. haucke@fmp-berlin.de.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2022 Mar; Vol. 29 (3), pp. 218-228. Date of Electronic Publication: 2022 Mar 07.
DOI: 10.1038/s41594-022-00730-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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