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 activity
2021
Computational 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
2019
Computational 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 kinase
2018
Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23
Liu L, Thaker TM, Freed DM, Frazier N, Malhotra K, Lemmon MA, Jura N. Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23. Structure 2018, 26: 270-281.e4. PMID: 29358026, PMCID: PMC5803352, DOI: 10.1016/j.str.2017.12.012.Peer-Reviewed Original ResearchConceptsLET-23Allosteric activatorEGF receptorAllosteric activation mechanismFull-length receptorCaenorhabditis elegansActive kinaseKinase domainAllosteric activationKinase activityReceptor dimersEGFR kinaseKinaseHuman EGFRDistinct rolesHuman counterpartActivation mechanismActivatorReceptorsElegansHeterodimerizationMutationsCrystal structureRegulationEGFR
2017
Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase.
Emptage RP, Lemmon MA, Ferguson KM. Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase. Biochemical Journal 2017, 474: 385-398. PMID: 27879374, PMCID: PMC5317272, DOI: 10.1042/bcj20160792.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsBinding SitesCloning, MolecularEnzyme AssaysEscherichia coliGene ExpressionHumansKineticsMitogen-Activated Protein Kinase 1Models, MolecularPeptidesPhospholipidsProtein BindingProtein Interaction Domains and MotifsProtein Structure, SecondaryRecombinant ProteinsScattering, Small AngleSubstrate SpecificityX-Ray DiffractionConceptsKA1 domainMAP/microtubule affinity-regulating kinasesMicrotubule affinity-regulating kinaseGroup of kinasesIntramolecular autoinhibitory interactionAnionic phospholipid bindingAnionic phospholipidsSite-directed mutagenesisAutoinhibitory interactionsRegulatory modulesAutoinhibitory roleProtein modulesMembrane-bound targetsRelated kinasesBind membranesFamily kinasesKinase domainProtein kinasePhospholipid activationC-terminusRegulatory mechanismsPhospholipid bindingMechanistic basisKinaseAutoinhibitory activity
2014
Putting together structures of epidermal growth factor receptors
Bessman NJ, Freed DM, Lemmon MA. Putting together structures of epidermal growth factor receptors. Current Opinion In Structural Biology 2014, 29: 95-101. PMID: 25460273, PMCID: PMC4268130, DOI: 10.1016/j.sbi.2014.10.002.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorGrowth factor receptorIntact epidermal growth factor receptorChemical biology methodsNumerous crystal structuresFactor receptorTyrosine kinase domainVariety of inhibitorsKinase domainExtracellular regionMembrane environmentIntracellular regionBiology methodsIntact receptorReceptorsCancer therapyNext challengeCrystal structureMembraneActivationRegionInhibitorsDomain
2013
Mechanism for activation of mutated epidermal growth factor receptors in lung cancer
Brewer M, Yun CH, Lai D, Lemmon MA, Eck MJ, Pao W. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: e3595-e3604. PMID: 24019492, PMCID: PMC3780914, DOI: 10.1073/pnas.1220050110.Peer-Reviewed Original ResearchConceptsWT epidermal growth factor receptorEpidermal growth factor receptorTyrosine kinase domainGrowth factor receptorConformational changesAsymmetric dimer interfaceMutant epidermal growth factor receptorAllosteric conformational changeAsymmetric dimer formationFactor receptorIntermolecular regulationKinase domainEGFR tyrosine kinase domainDimer interfaceMutantsM mutantActive conformation
2012
Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain
Park JH, Liu Y, Lemmon MA, Radhakrishnan R. Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochemical Journal 2012, 448: 417-423. PMID: 23101586, PMCID: PMC3507260, DOI: 10.1042/bj20121513.Peer-Reviewed Original ResearchAssessing the range of kinase autoinhibition mechanisms in the insulin receptor family
Artim SC, Mendrola JM, Lemmon MA. Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family. Biochemical Journal 2012, 448: 213-220. PMID: 22992069, PMCID: PMC3492919, DOI: 10.1042/bj20121365.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAmino Acid SequenceAntigens, CDCatalytic DomainCrystallography, X-RayEnzyme ActivationHumansIn Vitro TechniquesModels, MolecularMutationNeoplasmsProtein Structure, QuaternaryReceptor Tyrosine Kinase-like Orphan ReceptorsReceptor, InsulinReceptor, trkARecombinant Proteins
2011
Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases
Shih AJ, Telesco SE, Choi SH, Lemmon MA, Radhakrishnan R. Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases. Biochemical Journal 2011, 436: 241-251. PMID: 21426301, PMCID: PMC3138537, DOI: 10.1042/bj20101791.Peer-Reviewed Original ResearchConceptsErbB familyDifferent molecular contextsIntracellular kinase domainImportant regulatory elementsSrc kinase HckReceptor tyrosine kinasesHomologous receptor tyrosine kinasesSequence similarityKinase domainRegulatory elementsDimer interfaceSubdomain motionsInactive conformationKey residuesEGFR activationMolecular contextTyrosine kinasePresent molecular dynamics studyBond networkActive conformationConformational statesKinaseErbB kinasesMolecular dynamics analysisSalt bridge
2010
Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor
Alvarado D, Klein DE, Lemmon MA. Structural Basis for Negative Cooperativity in Growth Factor Binding to an EGF Receptor. Cell 2010, 142: 568-579. PMID: 20723758, PMCID: PMC2925043, DOI: 10.1016/j.cell.2010.07.015.Peer-Reviewed Original ResearchConceptsEGFR extracellular regionEpidermal growth factor receptorExtracellular regionEGF receptorDifferent signaling propertiesLigand-binding eventsLigand-induced dimerizationIntracellular tyrosine kinase domainNegative cooperativityCooperative ligand bindingTyrosine kinase domainAllosteric regulationEGF-binding sitesKinase domainFactor bindingGrowth factor receptorGrowth factor bindingStructural basisLigand bindingEGFR ligandsSignaling propertiesFactor receptorReduced affinityAsymmetric dimerUnoccupied sitesCell Signaling by Receptor Tyrosine Kinases
Lemmon MA, Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell 2010, 141: 1117-1134. PMID: 20602996, PMCID: PMC2914105, DOI: 10.1016/j.cell.2010.06.011.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesTyrosine kinaseIntracellular tyrosine kinase domainRecent structural studiesGrowth factor ligandsTyrosine kinase domainUnexpected diversityKinase domainCell signalingLigand bindingCellular responsesFactor ligandRTK mutationsKinaseStructural studiesActivationSignalingDiversityMutationsDimerizationMechanismBindingDomainErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation
Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 7692-7697. PMID: 20351256, PMCID: PMC2867849, DOI: 10.1073/pnas.1002753107.Peer-Reviewed Original Research
2009
The Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain
Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G. The Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain. Molecular Cell 2009, 34: 641-651. PMID: 19560417, PMCID: PMC2719887, DOI: 10.1016/j.molcel.2009.04.034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCarcinoma, Non-Small-Cell LungCell LineCell Transformation, NeoplasticChlorocebus aethiopsCOS CellsCrystallography, X-RayDimerizationErbB ReceptorsHumansMiceModels, MolecularMutagenesis, Site-DirectedMutationNIH 3T3 CellsPhosphorylationProtein Structure, TertiaryTyrosineConceptsEpidermal growth factor receptorActivation domainJuxtamembrane regionJM regionGrowth factor receptorIntracellular juxtamembrane regionEGF receptor functionAlanine-scanning mutagenesisFactor receptorTyrosine kinase activationAsymmetric dimerTyrosine kinase domainAutoinhibitory interactionsKinase domainCellular transformationScanning mutagenesisKinase activationEGFR activationC-lobeXenograft assayCancer mutationsC-terminal 19 residuesCrystallographic approachReceptor functionExtensive contactsRegulation of the epidermal growth factor receptor intracellular domain
Choi S, Lemmon M. Regulation of the epidermal growth factor receptor intracellular domain. The FASEB Journal 2009, 23: 883.2-883.2. DOI: 10.1096/fasebj.23.1_supplement.883.2.Peer-Reviewed Original ResearchC-terminal tailTyrosine kinase domainIntracellular domainJuxtamembrane regionJM regionEGFR intracellular domainEpidermal growth factor receptorC-tailEGFR extracellular regionC-tail regionReceptor intracellular domainEffects of mutationsReceptor tyrosine kinasesReceptor-receptor interactionsSmall-angle X-ray scatteringKinase assaysKinase domainGrowth factor receptorExtracellular regionReceptor dimerizationEGFR activationBaculovirus systemIntracellular dimerTyrosine kinaseDeletion mutations
2008
Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase
Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, Pal A, Bornmann WG, Lemmon MA, Cole PA, Leahy DJ. Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase. Structure 2008, 16: 460-467. PMID: 18334220, PMCID: PMC2858219, DOI: 10.1016/j.str.2007.12.016.Peer-Reviewed Original ResearchConceptsErbB4 kinaseEGF receptorBa/F3 cellsReceptor tyrosine kinasesMechanism of activationHER4/ErbB4ErbB family membersKinase domainHER2/ErbB2Kinase activationMutagenesis studiesTyrosine kinaseF3 cellsKinaseDimer conformationErbB familyNormal developmentInactive formAsymmetric dimerMammary glandErbB4ActivationFamily members
2006
EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer
Choi SH, Mendrola JM, Lemmon MA. EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 2006, 26: 1567-1576. PMID: 16953218, DOI: 10.1038/sj.onc.1209957.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorTyrosine kinase domainKinase domainEGF receptorRecent structural studiesSomatic mutationsCell surface EGF receptorsTyrosine kinase activityAbsence of EGFAutoinhibitory interactionsActivation loopErbB family membersGrowth factor receptorTyrosine phosphorylationEGFR tyrosine kinase domainKinase activityNull backgroundMechanistic basisOncogenic mutationsBiochemical propertiesCell surfaceCell lung carcinoma patientsFactor receptorMutationsLung carcinoma patients