2025
A triple-action inhibitory mechanism of allosteric TYK2-specific inhibitors
Wang J, Lomakin I, Batista V, Bunick C. A triple-action inhibitory mechanism of allosteric TYK2-specific inhibitors. Journal Of Investigative Dermatology 2025 PMID: 40378946, DOI: 10.1016/j.jid.2025.04.025.Peer-Reviewed Original ResearchJak-signal transducer and activatorAutoinhibited statePseudokinase domainIFN-induced gene expressionAtomic resolution structuresPhosphorylation of downstream proteinsAdenosine triphosphate bindingTyk2 kinaseTriphosphate bindingKinase domainActive stateResolution structureKinase activityTYK2Gene expressionStructural basisDownstream proteinsAllosteric drugsSteric clashesAllosteric inhibitorsInhibition mechanismMechanistic hypothesesKinaseBindingProtein
2024
Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling
Mühlenbeck H, Tsutsui Y, Lemmon M, Bender K, Zipfel C. Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling. ELife 2024, 12: rp92110. PMID: 39028038, PMCID: PMC11259431, DOI: 10.7554/elife.92110.Peer-Reviewed Original ResearchConceptsKinase domainReceptor kinasePhosphorylation-dependent conformational changesActive conformationIntragenic suppressor mutationsCo-receptor BAK1Kinase-dead variantPlant receptor kinasesProtein kinase domainLeucine-rich repeatNon-catalytic functionsIntracellular kinase domainCo-receptorLRR-RKsSuppressor mutationsTrans-phosphorylationPseudokinase domainActivation loopActive kinaseAllosteric activationTransmembrane signalingBAK1Immune signalingRegulate signalingSignaling activityAllosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling
Mühlenbeck H, Tsutsui Y, Lemmon M, Bender K, Zipfel C. Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling. ELife 2024, 12 DOI: 10.7554/elife.92110.4.Peer-Reviewed Original ResearchKinase domainReceptor kinasePhosphorylation-dependent conformational changesActive conformationIntragenic suppressor mutationsCo-receptor BAK1Kinase-dead variantPlant receptor kinasesProtein kinase domainLeucine-rich repeatNon-catalytic functionsIntracellular kinase domainCo-receptorLRR-RKsSuppressor mutationsTrans-phosphorylationPseudokinase domainActivation loopActive kinaseAllosteric activationTransmembrane signalingBAK1Immune signalingRegulate signalingSignaling activityModulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
Edman N, Phal A, Redler R, Schlichthaerle T, Srivatsan S, Ehnes D, Etemadi A, An S, Favor A, Li Z, Praetorius F, Gordon M, Vincent T, Marchiano S, Blakely L, Lin C, Yang W, Coventry B, Hicks D, Cao L, Bethel N, Heine P, Murray A, Gerben S, Carter L, Miranda M, Negahdari B, Lee S, Trapnell C, Zheng Y, Murry C, Schweppe D, Freedman B, Stewart L, Ekiert D, Schlessinger J, Shendure J, Bhabha G, Ruohola-Baker H, Baker D. Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies. Cell 2024, 187: 3726-3740.e43. PMID: 38861993, PMCID: PMC11246234, DOI: 10.1016/j.cell.2024.05.025.Peer-Reviewed Original ResearchConceptsIntracellular tyrosine kinase domainMitogen-activated protein kinase (MAPK) pathway activationDownstream signaling cascadesCyclic homo-oligomersTyrosine kinase domainReceptor valencyCell fateOligomeric assembliesKinase domainSignaling outcomesSignaling ligandsHomo-oligomersSplice variantsSignaling cascadesCytokine signalingExtracellular domainPathway signalingDevelopmental transitionsProtein building blocksVascular differentiationPathway activationVascular developmentComplexity of signalsModular assemblyTherapeutic applications
2022
RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features
Sultan M, Adawi M, Kol N, McCourt B, Adawi I, Baram L, Tal N, Werner L, Lev A, Snapper S, Barel O, Konnikova L, Somech R, Shouval D. RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features. Frontiers In Immunology 2022, 13: 1041315. PMID: 36466854, PMCID: PMC9716469, DOI: 10.3389/fimmu.2022.1041315.Peer-Reviewed Original ResearchConceptsInfantile-onset inflammatory bowel diseaseReceptor-interacting serine/threonine-protein kinase 1Serine/threonine-protein kinase 1Peripheral blood mononuclear cellsRole of RIPK1Immune cellsMultiple cell typesRIPK1 deficiencyKinase domainCrohn's diseasePatient 1Patient 2Perianal fistulasT cellsGenetic analysisProtein modelingKinase 1B cellsGenetic studiesAllogeneic hematopoietic stem cell transplantationPatients' peripheral blood mononuclear cellsImportant regulatorHematopoietic stem cell transplantationPathogenic genetic variantsCell typesMolecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)
Ha B, Yigit S, Natarajan N, Morse E, Calderwood D, Boggon T. Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Communications Biology 2022, 5: 1257. PMID: 36385162, PMCID: PMC9669019, DOI: 10.1038/s42003-022-04157-3.Peer-Reviewed Original ResearchConceptsP21-activated kinase 4Integrin adhesion receptorsMolecular basisAdhesion receptorsIntegrin β5Potential cellular rolesIntegrin β tailsKinase 4Membrane-proximal halfSubstrate-binding grooveSubstrate-binding siteSite-directed mutagenesisCellular rolesPhosphoacceptor sitesΒ tailExtracellular ligandsCytoplasmic signalingCytoplasmic tailKinase domainMultiple kinasesIntegrin complexΒ5 integrinsΒ5TailMutagenesisAutoinhibition 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 InterferometryA novel c.1937T>C (p.Leu646Pro) missense mutation in a patient with Leber congenital amaurosis
Kaur S, Sukhija J, Kaur A, Srivastava P, Katoch D, Singh S, Chaudhary K. A novel c.1937T>C (p.Leu646Pro) missense mutation in a patient with Leber congenital amaurosis. Journal Of American Association For Pediatric Ophthalmology And Strabismus 2022, 26: 34-35. PMID: 35101627, DOI: 10.1016/j.jaapos.2021.08.300.Peer-Reviewed Original ResearchConceptsLeber congenital amaurosisCongenital amaurosisComprehensive genotype-phenotype correlationMissense mutationsSluggish pupillary reactionInherited Retinal DystrophiesGenotype-phenotype correlationNormal fundusRetinal dystrophyTyrosine kinase domainGUCY2D geneExon 9Pupillary reactionExome sequencingPatientsLow visionAmaurosisLeberMutationsGenetic studiesHyperopiaGUCY2DKinase domainFundusNystagmus
2021
Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
Wu K, Wu H, Lyu W, Kim Y, Furdui CM, Anderson KS, Koleske AJ. Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation. Journal Of Biological Chemistry 2021, 297: 100883. PMID: 34144039, PMCID: PMC8259415, DOI: 10.1016/j.jbc.2021.100883.Peer-Reviewed Original ResearchConceptsAbl family kinasesFamily kinasesPlatelet-derived growth factor receptor betaGrowth factor receptor betaAbl familySrc homology 2 domainSrc homology 3 domainDiverse cellular stimuliPost-translational modificationsN-terminal halfNonreceptor tyrosine kinaseMultiple novel sitesAutoinhibited conformationSrc homologyCytoskeleton organizationCytoplasmic domainCellular stimuliKinase domainGrowth factor receptorReceptor betaKinase activityMolecular mechanismsTyrosine kinaseDirect bindingKinaseEnvironmental and sex-specific molecular signatures of glioma causation
Claus EB, Cannataro VL, Gaffney SG, Townsend JP. Environmental and sex-specific molecular signatures of glioma causation. Neuro-Oncology 2021, 24: 29-36. PMID: 33942853, PMCID: PMC8730771, DOI: 10.1093/neuonc/noab103.Peer-Reviewed Original ResearchConceptsIDH wild-type tumorsWild-type tumorsEnvironmental risk factorsIDH-mutant tumorsRisk factorsCases of gliomaMolecular signaturesPIK3CA mutationsPossible risk exposuresMutation subtypesCancer effectsExogenous exposureAdult gliomasTumorsWhole-exome sequencing dataGliomasKinase domainMutational signaturesCancer-causing mutationsMalesFemalesNon-coding regionsPIK3R1SexCancer mutational signaturesComputational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation
Patil K, Jordan EJ, Park JH, Suresh K, Smith CM, Lemmon AA, Mossé YP, Lemmon MA, Radhakrishnan R. Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2019132118. PMID: 33674381, PMCID: PMC7958353, DOI: 10.1073/pnas.2019132118.Peer-Reviewed Original Research
2020
Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation
Bhattacharyya M, Lee YK, Muratcioglu S, Qiu B, Nyayapati P, Schulman H, Groves JT, Kuriyan J. Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation. ELife 2020, 9: e53670. PMID: 32149607, PMCID: PMC7141811, DOI: 10.7554/elife.53670.Peer-Reviewed Original ResearchConceptsInhibitory autophosphorylationResidue linkerDependent protein kinase IISingle-molecule assaysMammalian cell expressionProtein kinase IICaMKII variantsShort linkerTransphosphorylation ratesKinase domainCaMKII holoenzymeKinase IIAutophosphorylationHoloenzymeFlexible linkerPrincipal isoformCalcium signalsRelative levelsIsoformsCaMKIIHuman CaCell expressionLinkerVariantsSequence
2019
Structural Insights into the Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII).
Bhattacharyya M, Karandur D, Kuriyan J. Structural Insights into the Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII). Cold Spring Harbor Perspectives In Biology 2019, 12: a035147. PMID: 31653643, PMCID: PMC7263085, DOI: 10.1101/cshperspect.a035147.Peer-Reviewed Original ResearchConceptsDependent protein kinase IIProtein kinase IIKinase domainKinase IISerine/threonine kinaseSpecialized isoformIntact holoenzymeThreonine kinaseCaMKII functionCaMKII holoenzymeSubunit exchangeStructural insightsRecent electron microscopic investigationsCaMKII activityStructural mechanismsFlexible linkerCardiac signalingCentral hubHoloenzymeCaMKIICurrent understandingKey roleKinaseSignalingElectron microscopic investigationsThe subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences
Sun X, Su VL, Calderwood DA. The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences. Journal Of Biological Chemistry 2019, 294: 14319-14332. PMID: 31391252, PMCID: PMC6768646, DOI: 10.1074/jbc.ra119.007692.Peer-Reviewed Original ResearchConceptsCell-cell contactCell-cell junctionsPolybasic sequenceP21-activated kinaseSmall GTPases RacVariable regionsCell-cell boundariesPAK regulationDomain organizationCdc42 bindingAdhesion dynamicsCRIB domainGTPases RacSubcellular localizationTruncation mutantsKinase domainKinase effectorsCellular signalsExtensive similaritySequence regionsPAK1Cell adhesionCdc42PAKKinaseComputational algorithms for in silico profiling of activating mutations in cancer
Jordan EJ, Patil K, Suresh K, Park JH, Mosse YP, Lemmon MA, Radhakrishnan R. Computational algorithms for in silico profiling of activating mutations in cancer. Cellular And Molecular Life Sciences 2019, 76: 2663-2679. PMID: 30982079, PMCID: PMC6589134, DOI: 10.1007/s00018-019-03097-2.Peer-Reviewed Original ResearchConceptsTarget proteinsSingle nucleotide polymorphismsB-RafSerine/threonine-protein kinase B-RafDifferent target proteinsEffects of mutationsStructure-based computational approachKinase domainStructure-based methodsStructure-based modelProtein structureProtein activationSilico profilingAnaplastic lymphoma kinaseInteraction of inhibitorsMutational landscapeHuman cancersPoint mutationsProteinMutationsMutational patternsDifferent mutationsActivation statusComputational approachLymphoma kinaseChapter 20 Drug Repurposing by Connectivity Mapping and Structural Modeling
Iqbal J, Yuen T, Zaidi N, Kim S, Zaidi S, Zallone A, Zaidi M, Sun L, Haider S. Chapter 20 Drug Repurposing by Connectivity Mapping and Structural Modeling. 2019, 609-623. DOI: 10.1016/b978-0-12-816125-8.00020-1.Peer-Reviewed Original ResearchEGF-induced cell proliferationReduced Akt phosphorylationConnectivity mapsHuman EGFRLung cancer cellsKinase domainNon-small cell lung cancer cellsReduced cell viabilityOsteoclast formation in vitroChronic inflammatory diseaseEGFR-driven cancersTyrphostin AG1478Formation in vitroAkt phosphorylationIn silico modelsIncreased apoptosisE746-A750Cancer cellsMRNA microarrayPARP inhibitorsActivating mutationsBisphosphonate actionBisphosphonatesInflammatory diseasesOsteoprotective action
2018
Cooperation between SYK and ZAP70 Kinases As a Driver of Oncogenic BCR-Signaling in B-Cell Malignancies
Sadras T, Cutler J, Aguade-Gorgorio J, Chen Z, Cosgun K, Pandey A, Muschen M. Cooperation between SYK and ZAP70 Kinases As a Driver of Oncogenic BCR-Signaling in B-Cell Malignancies. Blood 2018, 132: 3922. DOI: 10.1182/blood-2018-99-116954.Peer-Reviewed Original ResearchSpleen tyrosine kinaseSH2 domainZAP70 kinaseKinase domainCarboxy-terminal kinase domainLinker regionT cell receptorSurvival signalsBCR signalingTyrosine kinaseChronic lymphocytic leukemiaTandem SH2 domainsProximal signal transductionAmino acid insertB-cell malignanciesBCR-mediated signalsB cellsAlternative splice variantsNegative B cell selectionDifferential interactomeProteomic approachInterdomain BZAP70 proteinBCR componentsSignal transductionTwo Conserved Amino Acids within the NSs of Severe Fever with Thrombocytopenia Syndrome Phlebovirus Are Essential for Anti-interferon Activity
Moriyama M, Igarashi M, Koshiba T, Irie T, Takada A, Ichinohe T. Two Conserved Amino Acids within the NSs of Severe Fever with Thrombocytopenia Syndrome Phlebovirus Are Essential for Anti-interferon Activity. Journal Of Virology 2018, 92: 10.1128/jvi.00706-18. PMID: 30021900, PMCID: PMC6146818, DOI: 10.1128/jvi.00706-18.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceConserved SequenceGene Expression RegulationHost-Pathogen InteractionsHumansInfluenza A Virus, H1N1 SubtypeInterferon Regulatory Factor-3Interferon-betaInterleukin-1betaNLR Family, Pyrin Domain-Containing 3 ProteinPhlebotomus FeverPhlebovirusPhosphorylationPromoter Regions, GeneticProtein Serine-Threonine KinasesProtein TransportSequence AlignmentSeverity of Illness IndexSignal TransductionUbiquitinationViral Nonstructural ProteinsViruses, UnclassifiedConceptsTANK-binding kinase 1SFTSV nonstructural proteinInterferon regulatory factor 3Nonstructural proteinsHost antiviral responseCytoplasmic structuresAmino acidsInterferon-beta productionKinase 1N-terminal kinase domainTick-borne phlebovirusesSFTS phlebovirusConserved amino acidsAntiviral responseC-terminal regionN-terminal regionIFN-β promoter activityPosition 21Host antiviral strategyHost innate immune systemThrombocytopenia syndrome phlebovirusRegulatory factor 3Host interferon responseKinase domainIFN-β productionPharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14
Nakazono A, Adachi N, Takahashi H, Seki T, Hamada D, Ueyama T, Sakai N, Saito N. Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14. Journal Of Biological Chemistry 2018, 293: 14758-14774. PMID: 30093405, PMCID: PMC6153279, DOI: 10.1074/jbc.ra118.002913.Peer-Reviewed Original ResearchConceptsSpinocerebellar ataxia type 14Pharmacological up-regulationC2 domainHeat shock proteinsDominant-inherited neurodegenerative diseaseRefolding of misfolded proteinsUp-regulation of HSP70Type 14Amyloid-like protein aggregatesAmyloid-like fibril formationHerbimycin AIntracellular formationApoptotic cell deathShock proteinsLevels of apoptotic cell deathEndogenous regulatorProtein chaperonesPrimary cultured Purkinje cellsKinase domainProtein aggregationPurkinje cellsCell deathFibril formationInduction of heat shock proteinsHeat shock protein 70Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain
Emptage RP, Lemmon MA, Ferguson KM, Marmorstein R. Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure 2018, 26: 1137-1143.e3. PMID: 30099988, PMCID: PMC6092042, DOI: 10.1016/j.str.2018.05.008.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCheckpoint Kinase 1Cloning, MolecularCrystallography, X-RayEscherichia coliGene ExpressionGenetic VectorsHumansKineticsModels, MolecularMutationPeptidesProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsProtein Serine-Threonine KinasesRecombinant ProteinsStructural Homology, ProteinSubstrate SpecificityThermodynamicsConceptsKA1 domainSer/Thr protein kinaseKinase structureRelated kinasesUBA domainKinase domainProtein kinaseStructural basisC-terminusUnexpected interfaceC-lobeKinaseΑD helixPotential new avenuesAutoinhibitoryData implicateDomain surfaceDomainNew avenuesYeastAutoinhibitionCrystal structureHelixAlzheimer's diseaseVariants
This site is protected by hCaptcha and its Privacy Policy and Terms of Service apply