7thy

Structure of Leucine Rich Repeat Kinase 2's ROC domain interacting with the microtubule facing the minus end

spinqualitylabelsall models 7thy, resolution 5.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7thy is a 1 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 5.2Å Ligands: GDP 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 one of the most commonly mutated genes in familial Parkinson's disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-EM structure of the catalytic half of LRRK2, containing its kinase, in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2 but is not linked to PD. Although LRRK1's structure is similar to that of LRRK2, we find that LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2's GTPase that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2's kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors. Structural basis for Parkinson's disease-linked LRRK2's binding to microtubules.,Snead DM, Matyszewski M, Dickey AM, Lin YX, Leschziner AE, Reck-Peterson SL Nat Struct Mol Biol. 2022 Dec;29(12):1196-1207. doi: 10.1038/s41594-022-00863-y. , Epub 2022 Dec 12. PMID:36510024 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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