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

DOI: 10.7554/eLife.64922 DOI Help

Authors: Jone Paesmans (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Ella Martin (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Babette Deckers (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Marjolijn Berghmans (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Ritika Sethi (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Yannick Loeys (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Els Pardon (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Jan Steyaert (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel) , Patrik Verstreken (VIB-KU Leuven Center for Brain and Disease Research; KU Leuven) , Christian Galicia (VIB-VUB Center for Structural Biology, Brussels; Vrije Universiteit Brussel) , Wim Versees (VIB-VUB Center for Structural Biology; Vrije Universiteit Brussel)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 9

State: Published (Approved)
Published: December 2020

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Documents:
elife-64922-v2.pdf