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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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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. |
format | Online Article Text |
id | pubmed-8930771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
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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