A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations

Jone Paesmans, Ella Martin, Babette Deckers, Marjolijn Berghmans, Ritika Sethi, Yannick Loeys, Els Pardon, Jan Steyaert, Patrik Verstreken, Christian Galicia, Wim Versées

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
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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)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..

Original languageEnglish
Article numbere64922
Pages (from-to)1-27
Number of pages27
JournaleLife
Volume9
DOIs
Publication statusPublished - 22 Dec 2020

Bibliographical note

© 2020, Paesmans et al.

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