6vp8

Cryo-EM structure of the C-terminal half of the Parkinson's Disease-linked protein Leucine Rich Repeat Kinase 2 (LRRK2)

spinqualitylabelsall models 6vp8, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vp8 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.5Å Ligands: TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease LRRK2_HUMAN Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:607060. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients. Function LRRK2_HUMAN May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes. Publication Abstract from PubMed Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease (PD)(1) and is also linked to its idiopathic form(2). LRRK2 is proposed to function in membrane trafficking(3) and co-localizes with microtubules(4). Despite LRRK2's fundamental importance for understanding and treating PD, there is limited structural information on it. Here we report the 3.5A structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported 14A cryo-electron tomography in situ structure(5). We propose that the conformation of LRRK2's kinase domain regulates its microtubule interaction, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin-1 and cytoplasmic dynein-1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce LRRK2 filament formation in cells, while those that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors. Structure of LRRK2 in Parkinson's disease and model for microtubule interaction.,Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Bohning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL, Leschziner AE Nature. 2020 Aug 19. pii: 10.1038/s41586-020-2673-2. doi:, 10.1038/s41586-020-2673-2. PMID:32814344 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also LRRK2 3D structures Serine/threonine protein kinase 3D structures

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