Projecten per jaar
Abstract
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)P 3 , 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.
Datum van beschikbaarheid | 30 dec 2020 |
---|---|
Uitgever | Protein Data Bank in Europe |
Format
- Format
-
FWOAL1054: Inzicht in de structuur, functie en het mechanisme van Synaptojanin1 in de context van neurologische ziekten
1/01/22 → 31/12/25
Project: Fundamenteel
Onderzoekersoutput
- 1 Article
-
A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations
Paesmans, J., Martin, E., Deckers, B., Berghmans, M., Sethi, R., Loeys, Y., Pardon, E., Steyaert, J., Verstreken, P., Galicia, C. & Versées, W., 22 dec 2020, In: eLife. 9, blz. 1-27 27 blz., e64922.Onderzoeksoutput: Article › peer review
Open AccessBestand9 Citaten (Scopus)124 Downloads (Pure)