2022
Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants
Bircher JE, Corcoran EE, Lam TT, Trnka MJ, Koleske AJ. Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants. Journal Of Biological Chemistry 2022, 298: 102361. PMID: 35963430, PMCID: PMC9467883, DOI: 10.1016/j.jbc.2022.102361.Peer-Reviewed Original ResearchConceptsSpectrin repeatsGEF1 domainPleckstrin homology regionExchange factor domainKey regulatory mechanismCytoskeletal regulatory proteinsSmall GTPase Rac1Autoinhibitory constraintsAccessory domainsNeurodevelopmental disordersGEF activityMultiple neurodevelopmental disordersKinase domainHomology regionProtein TrioGTPase Rac1Regulatory proteinsRegulatory mechanismsFactor domainSRS-6Genetic variantsGef1Disease variantsEnzymatic activityBio-Layer Interferometry
2020
Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi
Lim C, Berk JM, Blaise A, Bircher J, Koleske AJ, Hochstrasser M, Xiong Y. Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 30380-30390. PMID: 33184172, PMCID: PMC7720168, DOI: 10.1073/pnas.2018163117.Peer-Reviewed Original ResearchConceptsBacterial GEFStructure-guided mutational analysisExchange factor domainRho family GTPasesObvious sequence similarityRho GTPases Rac1Pathogen Orientia tsutsugamushiAlters cell morphologyInteraction screenConvergent evolutionGEF domainHost interactorsExchange factorNucleotide displacementGEF activityCellular processesSequence similarityCytoskeletal structuresGTPases Rac1Ectopic expressionMutational analysisGEFRac1Factor domainPathogenic bacterium
2016
Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma
Lissanu Deribe Y, Shi Y, Rai K, Nezi L, Amin S, Wu C, Akdemir K, Mahdavi M, Peng Q, Chang Q, Hornigold K, Arold S, Welch H, Garraway L, Chin L. Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e1296-e1305. PMID: 26884185, PMCID: PMC4780599, DOI: 10.1073/pnas.1513801113.Peer-Reviewed Original ResearchConceptsPREX2 mutationsCross-species gene expression analysisGuanine nucleotide exchange factor activityNucleotide exchange factor activityGene expression regulationPI3K/PTEN/Akt pathwayExchange factor activityMelanoma developmentPTEN/AKT pathwayCell cycle regulatorsGene expression analysisExpression regulationGEF activityCytoskeleton organizationCDKN1C geneRegulatory regionsExpression analysisGene expressionCycle regulatorsDNA hypomethylationCell cycleChromosome 11Tumor suppressorBiological pathwaysMechanistic basis
2015
Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation
Coleman BD, Marivin A, Parag-Sharma K, DiGiacomo V, Kim S, Pepper JS, Casler J, Nguyen LT, Koelle MR, Garcia-Marcos M. Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation. Molecular Biology And Evolution 2015, 33: 820-837. PMID: 26659249, PMCID: PMC4760084, DOI: 10.1093/molbev/msv336.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAnimalsBiological EvolutionCaenorhabditis elegansCaenorhabditis elegans ProteinsEvolution, MolecularGene ExpressionGTP-Binding ProteinsGuanine Nucleotide Exchange FactorsModels, MolecularProtein BindingProtein ConformationProtein Interaction Domains and MotifsProtein MultimerizationReceptors, G-Protein-CoupledSignal TransductionConceptsGBA motifGEF activityG protein activationTrimeric G-protein signalingGuanine nucleotide exchange factor activityProtein activationG proteinsMammalian Gα subunitsG protein-mediated signalingMotif-containing proteinsGPCR-independent mechanismReceptor-independent G-protein activationExchange factor activityG protein signalingProtein-mediated signalingMammalian cell behaviorGOA-1Evolutionary conservationDivergent proteinsCaenorhabditis elegansBioinformatics searchGα subunitsMost invertebratesProtein signalingAccessory proteinsPTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion
Mense SM, Barrows D, Hodakoski C, Steinbach N, Schoenfeld D, Su W, Hopkins BD, Su T, Fine B, Hibshoosh H, Parsons R. PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion. Science Signaling 2015, 8: ra32. PMID: 25829446, PMCID: PMC4874664, DOI: 10.1126/scisignal.2005840.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell MovementDNA PrimersFluorescent Antibody TechniqueGene Knockout TechniquesGenetic VectorsGuanine Nucleotide Exchange FactorsHumansImmunoblottingImmunoprecipitationLentivirusMiceNeoplasm InvasivenessPolymerase Chain ReactionPTEN Phosphohydrolaserac1 GTP-Binding ProteinRNA, Small InterferingStatistics, NonparametricConceptsLipid phosphatase activityPTEN-mediated inhibitionGEF activityCancer mutantsCell migrationNucleotide exchange assaysPhosphatase activityTumor suppressor PTENMouse embryonic fibroblastsTumor cell invasionPI3K pathwayHuman tumor dataKinase AktSuppressor PTENTail domainEmbryonic fibroblastsGTPase Rac1PREX2 mutationsImmortalized melanocytesMutantsCell invasionHigh PTEN expressionK pathwayRac1Breast cancer cell lines
2014
AMPylation Is Critical for Rab1 Localization to Vacuoles Containing Legionella pneumophila
Hardiman CA, Roy CR. AMPylation Is Critical for Rab1 Localization to Vacuoles Containing Legionella pneumophila. MBio 2014, 5: 10.1128/mbio.01035-13. PMID: 24520063, PMCID: PMC3950522, DOI: 10.1128/mbio.01035-13.Peer-Reviewed Original ResearchConceptsLCV membraneEffector proteinsGEF activityEndoplasmic reticulumIntracellular pathogen Legionella pneumophilaLegionella effector proteinsType IV secretion systemExchange factor domainLegionella pneumophilaMembrane-bound compartmentsMembrane-bound organellesPathogen Legionella pneumophilaAccumulation of GTPHost cell functionsAMPylation activityDrrA proteinRab1 proteinRab1 recruitmentLegionella effectorsNucleotidyltransferase domainAMPylationSecretion systemPosttranslational modificationsRab1GTPase
2011
Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors
Lee C, Shin E, Hong J, Schwartz M, Kim E. Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors. The FASEB Journal 2011, 25: 930.9-930.9. DOI: 10.1096/fasebj.25.1_supplement.930.9.Peer-Reviewed Original ResearchFocal complex formationDbl family guanineMyosin IIExchange factorFamily guanineATPase activityNonmuscle myosin IIComplex formationSpatiotemporal regulationGEF activityAdhesion dynamicsCdc42 GTPasesRho GTPasesCdc42 activationLamellipodial protrusionCell protrusionsActomyosin contractionGEFFunctional linkNIH3T3 fibroblastsCell migrationGTPasesCatalytic siteHomology modulesGuanine
2010
Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors: a possible link to Rho family GTPases
Lee CS, Choi CK, Shin EY, Schwartz MA, Kim EG. Myosin II directly binds and inhibits Dbl family guanine nucleotide exchange factors: a possible link to Rho family GTPases. Journal Of Cell Biology 2010, 190: 663-674. PMID: 20713598, PMCID: PMC2928003, DOI: 10.1083/jcb.201003057.Peer-Reviewed Original ResearchMeSH KeywordsActomyosinAnimalsBinding Sitescdc42 GTP-Binding ProteinCell AdhesionCell MovementEnzyme ActivationGuanine Nucleotide Exchange FactorsHumansJurkat CellsMiceMyosin Type IINIH 3T3 CellsPlatelet-Derived Growth FactorProtein Bindingrac1 GTP-Binding ProteinRatsRecombinant Fusion Proteinsrho GTP-Binding ProteinsRho Guanine Nucleotide Exchange FactorsRNA, Small InterferingConceptsFocal complex formationDbl family guanineMyosin IIExchange factorFamily guanineATPase activityNonmuscle myosin IIComplex formationGEF activitySpatiotemporal regulationRho familyCdc42 GTPasesAdhesion dynamicsRho GTPasesCdc42 activationLamellipodial protrusionCell protrusionsActomyosin contractionGEFNIH3T3 fibroblastsFunctional linkCell migrationGTPasesCatalytic siteHomology modules
2009
Kinetic Analysis of the Guanine Nucleotide Exchange Activity of TRAPP, a Multimeric Ypt1p Exchange Factor
Chin HF, Cai Y, Menon S, Ferro-Novick S, Reinisch KM, De La Cruz EM. Kinetic Analysis of the Guanine Nucleotide Exchange Activity of TRAPP, a Multimeric Ypt1p Exchange Factor. Journal Of Molecular Biology 2009, 389: 275-288. PMID: 19361519, PMCID: PMC2770256, DOI: 10.1016/j.jmb.2009.03.068.Peer-Reviewed Original ResearchConceptsMembrane trafficExchange factorGuanine nucleotide exchange activityRab GTPase Ypt1pLarge multimeric assembliesNucleotide exchange activityThermodynamic linkage analysisWeak thermodynamic couplingTRAPP complexesStable ternary complexTRAPP subunitsGEF activityYpt1pNucleotide bindingMultimeric assembliesNucleotide exchangeNucleotide dissociationNucleotide affinityLinkage analysisIndependent pathwaysGEF systemTernary complexExchange activityTRAPPOverall net change
2007
Function of the N-terminus of zizimin1: autoinhibition and membrane targeting
Meller N, Westbrook MJ, Shannon JD, Guda C, Schwartz MA. Function of the N-terminus of zizimin1: autoinhibition and membrane targeting. Biochemical Journal 2007, 409: 525-533. PMID: 17935486, PMCID: PMC2740492, DOI: 10.1042/bj20071263.Peer-Reviewed Original ResearchConceptsGEF domainCZH proteinsRho family small GTPasesPH domain bindsCdc42-specific GEFMultiple cellular functionsBasis of homologyN-terminal regionSmall GTPasesDomain bindsGEF activityRho proteinsCellular functionsRho-GEFsNovel functionN-terminusCritical regulatorStructural domainsLimited proteolysisZizimin1ProteinBindsDomainMembraneGTPases
2006
The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity
Baumeister MA, Rossman KL, Sondek J, Lemmon MA. The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity. Biochemical Journal 2006, 400: 563-572. PMID: 17007612, PMCID: PMC1698603, DOI: 10.1042/bj20061020.Peer-Reviewed Original ResearchActivated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts
Sakai H, Chen Y, Itokawa T, Yu KP, Zhu ML, Insogna K. Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Bone 2006, 39: 1290-1301. PMID: 16950670, DOI: 10.1016/j.bone.2006.06.012.Peer-Reviewed Original ResearchMeSH KeywordsActinsAndrostadienesAnimalsBiological Transport, Activecdc42 GTP-Binding ProteinCells, CulturedCytoskeletonEnzyme InhibitorsGuanosine TriphosphateHumansMacrophage Colony-Stimulating FactorMiceModels, BiologicalOsteoclastsPhosphoinositide-3 Kinase InhibitorsProtein BindingProto-Oncogene Proteins c-vavPseudopodiarac GTP-Binding ProteinsRatsReceptor, Macrophage Colony-Stimulating FactorRecombinant ProteinsSignal TransductionWortmanninConceptsCSF-1GEF activityCytoskeletal remodelingGTPase activityAssociation of VavC-fmsRac GTPase activityDominant negative Cdc42Dominant-negative RacCSF-1 receptorInhibitors of PI3CSF-1 treatmentTarget GTPaseActive RacExchange factorActive Cdc42Actin reorganizationLamellipodia formationPhosphotyrosine contentC-SrcPlasma membraneInhibitor of RhoARapid translocationVavRac translocation
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