Background: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson's disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro.
Methodology/principal Findings: Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro and in vivo. GTPase activity of full-length LRRK2 increases in the presence of recombinant ARHGEF7. Interestingly, LRRK2 phosphorylates ARHGEF7 in vitro at previously unknown phosphorylation sites. We provide evidence that ARHGEF7 might act as a guanine nucleotide exchange factor for LRRK2 and that R1441C mutant LRRK2 with reduced GTP hydrolysis activity also shows reduced binding to ARHGEF7.
Conclusions/significance: Downstream effects of phosphorylation of ARHGEF7 through LRRK2 could be (i) a feedback control mechanism for LRRK2 activity as well as (ii) an impact of LRRK2 on actin cytoskeleton regulation. A newly identified familial mutation N1437S, localized within the GTPase domain of LRRK2, further underlines the importance of the GTPase domain of LRRK2 in Parkinson's disease pathogenesis.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2966438 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013762 | PLOS |
Publication Analysis
Top Keywords
Similar Publications
Targeting Tiam1 enhances hippocampal-dependent learning and memory in the adult brain and promotes NMDA receptor-mediated synaptic plasticity and function.
J Neurosci
December 2024
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood.
View Article and Find Full Text PDFRNA Order Regulates Its Interactions with Zwitterionic Lipid Bilayers.
Nano Lett
December 2024
Department of Biology, University of Fribourg, Chemin du Musée 10, CH-1700 Fribourg, Switzerland.
RNA-lipid interactions directly influence RNA activity, which plays a crucial role in the development of new applications in medicine and biotechnology. However, while specific preferential behaviors between RNA and lipid bilayers have been identified experimentally, their molecular origin remains unexplored. Here we use molecular dynamics simulations to investigate the interaction between RNA and membranes composed of zwitterionic lipids at the atomistic level.
View Article and Find Full Text PDFVesicle trafficking mediated by small GTPase CfRab6 in association with CfRic1 and CfRgp1 governs growth, conidiation, and pathogenicity of Colletotrichum fructicola.
Int J Biol Macromol
December 2024
College of Forestry, Central South University of Forestry and Technology, Changsha 410004, China; Key Laboratory for Non-wood Forest Cultivation and Conservation of Ministry of Education, Changsha 410004, China; Hunan Provincial Key Laboratory for Control of Forest Diseases and Pests, Changsha 410004, China. Electronic address:
Small GTPase of the Rab family functions as molecular switch in vesicle trafficking, regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In our ongoing efforts to study the pathogenesis of Colletotrichum fructicola, the causal agent of anthracnose in edible-oil plant Camellia oleifera, we identified CfRab6 as the Rab GTPase and characterized its roles in C. fructicola.
View Article and Find Full Text PDFIntegrated NMR-crystallography-computational approach for molecular recognition studies of human Gαi3 protein by a small molecule inhibitor.
Int J Biol Macromol
December 2024
Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia 46010, Spain; Centro de Investigación Príncipe Felipe, Unidad Asociada a IBV, Valencia 46012, Spain. Electronic address:
The small molecule IGGi-11 targets Gαi subunits of heterotrimeric guanine nucleotide-binding proteins. Gα subunits are activated by G-protein-coupled receptors in response to extracellular stimuli by accelerating the exchange of GDP for GTP, but they are also activated by intracellular proteins like GIV, of which elevated levels correlate with increased cell migration and cancer metastasis. IGGi-11 disrupts the interaction of Gαi proteins with GIV and inhibits pro-invasive traits of metastatic breast cancer cells without interfering with GPCR signaling.
View Article and Find Full Text PDFEpac2-mediated synaptic insertion of Ca-permeable AMPARs in the nucleus accumbens contributes to incubation of cocaine craving.
Neuropsychopharmacology
December 2024
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
The accumulation of GluA2-lacking Ca-permeable AMPARs (CP-AMPARs) in the medium spiny neurons (MSNs) of the nucleus accumbens (NAc) is required for the expression of incubation of cocaine craving. The exchange protein directly activated by cAMP (Epac) is an intracellular effector of cAMP and a guanine nucleotide exchange factor for the small GTPase Rap1. Epac2 has been implicated in the trafficking of AMPA receptors at central synapses.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!