VPS34 complexes from a structural perspective
VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the phosphoinositide 3-kinase (PI3K) family. VPS34 has a simpler domain organization than class I PI3Ks, which belies the complexity of its quaternary organization, with the enzyme always functioning within larger...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520326365 |
| _version_ | 1818726435882270720 |
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| author | Yohei Ohashi Shirley Tremel Roger L. Williams |
| author_facet | Yohei Ohashi Shirley Tremel Roger L. Williams |
| author_sort | Yohei Ohashi |
| collection | DOAJ |
| description | VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the phosphoinositide 3-kinase (PI3K) family. VPS34 has a simpler domain organization than class I PI3Ks, which belies the complexity of its quaternary organization, with the enzyme always functioning within larger assemblies. PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. Because VPS34 can form a component of several distinct complexes, it enables independent regulation of various pathways that are controlled by PtdIns3P. Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. Autophagy has a complex association with cancer. In early stages, it inhibits tumorigenesis, but in later stages, it acts as a survival factor for tumors. Recently, various disease-associated somatic mutations were found in genes encoding complex I and II subunits. Lipid kinase activities of the complexes are also influenced by posttranslational modifications (PTMs). Mapping PTMs and somatic mutations on three-dimensional models of the complexes suggests mechanisms for how these affect VPS34 activity. |
| first_indexed | 2024-12-17T21:58:10Z |
| format | Article |
| id | doaj.art-48fbe0ce81f941fb90b0a269938ec657 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T21:58:10Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-48fbe0ce81f941fb90b0a269938ec6572022-12-21T21:31:04ZengElsevierJournal of Lipid Research0022-22752019-02-01602229241VPS34 complexes from a structural perspectiveYohei Ohashi0Shirley Tremel1Roger L. Williams2MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United KingdomMRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United KingdomTo whom correspondence should be addressed; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United KingdomVPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the phosphoinositide 3-kinase (PI3K) family. VPS34 has a simpler domain organization than class I PI3Ks, which belies the complexity of its quaternary organization, with the enzyme always functioning within larger assemblies. PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. Because VPS34 can form a component of several distinct complexes, it enables independent regulation of various pathways that are controlled by PtdIns3P. Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. Autophagy has a complex association with cancer. In early stages, it inhibits tumorigenesis, but in later stages, it acts as a survival factor for tumors. Recently, various disease-associated somatic mutations were found in genes encoding complex I and II subunits. Lipid kinase activities of the complexes are also influenced by posttranslational modifications (PTMs). Mapping PTMs and somatic mutations on three-dimensional models of the complexes suggests mechanisms for how these affect VPS34 activity.http://www.sciencedirect.com/science/article/pii/S0022227520326365vacuolar protein sorting 34X-ray crystallographycryo-electron microscopyhydrogen-deuterium exchange mass-spectrometrylipid |
| spellingShingle | Yohei Ohashi Shirley Tremel Roger L. Williams VPS34 complexes from a structural perspective Journal of Lipid Research vacuolar protein sorting 34 X-ray crystallography cryo-electron microscopy hydrogen-deuterium exchange mass-spectrometry lipid |
| title | VPS34 complexes from a structural perspective |
| title_full | VPS34 complexes from a structural perspective |
| title_fullStr | VPS34 complexes from a structural perspective |
| title_full_unstemmed | VPS34 complexes from a structural perspective |
| title_short | VPS34 complexes from a structural perspective |
| title_sort | vps34 complexes from a structural perspective |
| topic | vacuolar protein sorting 34 X-ray crystallography cryo-electron microscopy hydrogen-deuterium exchange mass-spectrometry lipid |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520326365 |
| work_keys_str_mv | AT yoheiohashi vps34complexesfromastructuralperspective AT shirleytremel vps34complexesfromastructuralperspective AT rogerlwilliams vps34complexesfromastructuralperspective |