7a0v

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

spinqualitylabelsall models 7a0v, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7a0v is a 6 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: GOL, MG, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. 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, Versees W Elife. 2020 Dec 22;9:e64922. doi: 10.7554/eLife.64922. PMID:33349335 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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