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Structural basis of phosphatidylinositol 3-kinase C2α function

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 PI3...

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Autores principales: Lo, Wen-Ting, Zhang, Yingyi, Vadas, Oscar, Roske, Yvette, Gulluni, Federico, De Santis, Maria Chiara, Zagar, Andreja Vujicic, Stephanowitz, Heike, Hirsch, Emilio, Liu, Fan, Daumke, Oliver, Kudryashev, Misha, Haucke, Volker
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930771/
https://www.ncbi.nlm.nih.gov/pubmed/35256802
http://dx.doi.org/10.1038/s41594-022-00730-w
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author Lo, Wen-Ting
Zhang, Yingyi
Vadas, Oscar
Roske, Yvette
Gulluni, Federico
De Santis, Maria Chiara
Zagar, Andreja Vujicic
Stephanowitz, Heike
Hirsch, Emilio
Liu, Fan
Daumke, Oliver
Kudryashev, Misha
Haucke, Volker
author_facet Lo, Wen-Ting
Zhang, Yingyi
Vadas, Oscar
Roske, Yvette
Gulluni, Federico
De Santis, Maria Chiara
Zagar, Andreja Vujicic
Stephanowitz, Heike
Hirsch, Emilio
Liu, Fan
Daumke, Oliver
Kudryashev, Misha
Haucke, Volker
author_sort Lo, Wen-Ting
collection PubMed
description 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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spelling pubmed-89307712022-03-23 Structural basis of phosphatidylinositol 3-kinase C2α function Lo, Wen-Ting Zhang, Yingyi Vadas, Oscar Roske, Yvette Gulluni, Federico De Santis, Maria Chiara Zagar, Andreja Vujicic Stephanowitz, Heike Hirsch, Emilio Liu, Fan Daumke, Oliver Kudryashev, Misha Haucke, Volker Nat Struct Mol Biol Article 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. Nature Publishing Group US 2022-03-07 2022 /pmc/articles/PMC8930771/ /pubmed/35256802 http://dx.doi.org/10.1038/s41594-022-00730-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lo, Wen-Ting
Zhang, Yingyi
Vadas, Oscar
Roske, Yvette
Gulluni, Federico
De Santis, Maria Chiara
Zagar, Andreja Vujicic
Stephanowitz, Heike
Hirsch, Emilio
Liu, Fan
Daumke, Oliver
Kudryashev, Misha
Haucke, Volker
Structural basis of phosphatidylinositol 3-kinase C2α function
title Structural basis of phosphatidylinositol 3-kinase C2α function
title_full Structural basis of phosphatidylinositol 3-kinase C2α function
title_fullStr Structural basis of phosphatidylinositol 3-kinase C2α function
title_full_unstemmed Structural basis of phosphatidylinositol 3-kinase C2α function
title_short Structural basis of phosphatidylinositol 3-kinase C2α function
title_sort structural basis of phosphatidylinositol 3-kinase c2α function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8930771/
https://www.ncbi.nlm.nih.gov/pubmed/35256802
http://dx.doi.org/10.1038/s41594-022-00730-w
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