protein localization to ciliary membrane / peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / phagosome-lysosome fusion / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size ...protein localization to ciliary membrane / peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / phagosome-lysosome fusion / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / negative regulation of late endosome to lysosome transport / regulation of synaptic vesicle transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / amphisome / mitochondrion localization / cytoplasmic side of mitochondrial outer membrane / co-receptor binding / modulation by host of viral process / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / regulation of dopamine receptor signaling pathway / negative regulation of autophagosome assembly / positive regulation of microglial cell activation / neuron projection arborization / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / olfactory bulb development / RAB geranylgeranylation / regulation of protein kinase A signaling / positive regulation of intracellular protein transport / multivesicular body, internal vesicle / striatum development / melanosome organization / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / cellular response to dopamine / protein localization to membrane / cis-Golgi network / presynaptic cytosol / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / retrograde transport, endosome to Golgi / cellular detoxification / positive regulation of programmed cell death / Wnt signalosome / regulation of canonical Wnt signaling pathway / GTP metabolic process / negative regulation of protein processing / vacuole / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / negative regulation of GTPase activity / exploration behavior / autolysosome / regulation of locomotion / protein kinase A binding / Golgi-associated vesicle / neuromuscular junction development / regulation of synaptic vesicle exocytosis / PTK6 promotes HIF1A stabilization / clathrin binding / negative regulation of macroautophagy / dynein complex binding / positive regulation of receptor recycling / intracellular vesicle / regulation of mitochondrial fission / lysosome organization / intracellular distribution of mitochondria / endosome to lysosome transport / positive regulation of T cell receptor signaling pathway / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / Golgi organization / kinesin binding / endoplasmic reticulum exit site / microvillus / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / canonical Wnt signaling pathway / cellular response to manganese ion / endomembrane system / positive regulation of autophagy / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / JNK cascade / regulation of synaptic transmission, glutamatergic / synapse assembly / T cell activation / dendrite cytoplasm / excitatory postsynaptic potential 類似検索 - 分子機能
Ras-related protein Rab29/Rab38/Rab32 / C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / small GTPase Rab1 family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Leucine rich repeat ...Ras-related protein Rab29/Rab38/Rab32 / C-terminal of Roc (COR) domain / C-terminal of Roc, COR, domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / small GTPase Rab1 family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / WD40-repeat-containing domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性
National Institutes of Health/National Cancer Institute (NIH/NCI)
R00HL143037
米国
引用
ジャーナル: Science / 年: 2023 タイトル: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. 著者: Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun / 要旨: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles ...Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment.