A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations
Synaptojanin1 (Synj1) is a phosphoinositide phosphatase, important in clathrin uncoating during endocytosis of presynaptic vesicles. It was identified as a potential drug target for Alzheimer’s disease, Down syndrome, and TBC1D24-associated epilepsy, while also loss-of-function mutations in Synj1 ar...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/64922 |
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| author | Jone Paesmans Ella Martin Babette Deckers Marjolijn Berghmans Ritika Sethi Yannick Loeys Els Pardon Jan Steyaert Patrik Verstreken Christian Galicia Wim Versées |
| author_facet | Jone Paesmans Ella Martin Babette Deckers Marjolijn Berghmans Ritika Sethi Yannick Loeys Els Pardon Jan Steyaert Patrik Verstreken Christian Galicia Wim Versées |
| author_sort | Jone Paesmans |
| collection | DOAJ |
| description | Synaptojanin1 (Synj1) is a phosphoinositide phosphatase, important in clathrin uncoating during endocytosis of presynaptic vesicles. It was identified as a potential drug target for Alzheimer’s disease, Down syndrome, and TBC1D24-associated epilepsy, while also loss-of-function mutations in Synj1 are associated with epilepsy and Parkinson’s disease. Despite its involvement in a range of disorders, structural, and detailed mechanistic information regarding the enzyme is lacking. Here, we report the crystal structure of the 5-phosphatase domain of Synj1. Moreover, we also present a structure of this domain bound to the substrate diC8-PI(3,4,5)P3, providing the first image of a 5-phosphatase with a trapped substrate in its active site. Together with an analysis of the contribution of the different inositide phosphate groups to catalysis, these structures provide new insights in the Synj1 mechanism. Finally, we analysed the effect of three clinical missense mutations (Y793C, R800C, Y849C) on catalysis, unveiling the molecular mechanisms underlying Synj1-associated disease. |
| first_indexed | 2024-04-11T08:59:32Z |
| format | Article |
| id | doaj.art-7af11ac4f55145eba6933fc35aa0a442 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T08:59:32Z |
| publishDate | 2020-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7af11ac4f55145eba6933fc35aa0a4422022-12-22T04:32:49ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.64922A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutationsJone Paesmans0https://orcid.org/0000-0002-3292-4609Ella Martin1https://orcid.org/0000-0002-9607-7074Babette Deckers2https://orcid.org/0000-0002-3855-4776Marjolijn Berghmans3https://orcid.org/0000-0002-8699-6915Ritika Sethi4Yannick Loeys5Els Pardon6https://orcid.org/0000-0002-2466-0172Jan Steyaert7https://orcid.org/0000-0002-3825-874XPatrik Verstreken8Christian Galicia9https://orcid.org/0000-0001-6080-7533Wim Versées10https://orcid.org/0000-0002-4695-696XVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumVIB-VUB Center for Structural Biology, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, BelgiumSynaptojanin1 (Synj1) is a phosphoinositide phosphatase, important in clathrin uncoating during endocytosis of presynaptic vesicles. It was identified as a potential drug target for Alzheimer’s disease, Down syndrome, and TBC1D24-associated epilepsy, while also loss-of-function mutations in Synj1 are associated with epilepsy and Parkinson’s disease. Despite its involvement in a range of disorders, structural, and detailed mechanistic information regarding the enzyme is lacking. Here, we report the crystal structure of the 5-phosphatase domain of Synj1. Moreover, we also present a structure of this domain bound to the substrate diC8-PI(3,4,5)P3, providing the first image of a 5-phosphatase with a trapped substrate in its active site. Together with an analysis of the contribution of the different inositide phosphate groups to catalysis, these structures provide new insights in the Synj1 mechanism. Finally, we analysed the effect of three clinical missense mutations (Y793C, R800C, Y849C) on catalysis, unveiling the molecular mechanisms underlying Synj1-associated disease.https://elifesciences.org/articles/64922inositol polyphosphate 5-phosphatasecatalytic mechanismenzyme-substrate complexepilepsyphosphoinositideParkinson's disease |
| spellingShingle | Jone Paesmans Ella Martin Babette Deckers Marjolijn Berghmans Ritika Sethi Yannick Loeys Els Pardon Jan Steyaert Patrik Verstreken Christian Galicia Wim Versées A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations eLife inositol polyphosphate 5-phosphatase catalytic mechanism enzyme-substrate complex epilepsy phosphoinositide Parkinson's disease |
| title | A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations |
| title_full | A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations |
| title_fullStr | A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations |
| title_full_unstemmed | A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations |
| title_short | A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations |
| title_sort | structure of substrate bound synaptojanin1 provides new insights in its mechanism and the effect of disease mutations |
| topic | inositol polyphosphate 5-phosphatase catalytic mechanism enzyme-substrate complex epilepsy phosphoinositide Parkinson's disease |
| url | https://elifesciences.org/articles/64922 |
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