7A0V

Crystal structure of the 5-phosphatase domain of Synaptojanin1 in complex with a nanobody

Summary for 7A0V

• Entry DOI: 10.2210/pdb7a0v/pdb
• Descriptor: Synaptojanin-1, Nanobody 13015, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: inositol polyphosphate 5-phosphatase, phosphoinositide, parkinson's disease, epilepsy, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 164005.07

Authors

Paesmans, J.,Galicia, C.,Martin, E.,Versees, W. (deposition date: 2020-08-11, release date: 2020-12-30, Last modification date: 2024-10-16)

Primary citation

Paesmans, J.,Martin, E.,Deckers, B.,Berghmans, M.,Sethi, R.,Loeys, Y.,Pardon, E.,Steyaert, J.,Verstreken, P.,Galicia, C.,Versees, W.
A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations.
Elife, 9:-, 2020

PubMed 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, 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.

PubMed: 33349335
DOI: 10.7554/eLife.64922

Experimental method

X-RAY DIFFRACTION (2.3 Å)