Featured Publications
Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity
Kuzina ES, Ung PM, Mohanty J, Tome F, Choi J, Pardon E, Steyaert J, Lax I, Schlessinger A, Schlessinger J, Lee S. Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 7819-7824. PMID: 30944224, PMCID: PMC6475419, DOI: 10.1073/pnas.1822055116.Peer-Reviewed Original ResearchConceptsFGF receptorsPleiotropic cellular responsesFibroblast growth factor (FGF) familyPrimary high-affinity receptorsKlotho proteinChimeric mutantsGrowth factor familyCatalytic subunitFGFR functionRegulatory interactionsTerminal tailPleiotropic cellular effectsFactor familyP motifS motifExtracellular domainMolecular mechanismsIntracellular signalingCellular responsesSame binding siteCellular effectsGeneral mechanismEndocrine FGFsBinary complexBinding sitesInhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration
Lee S, Greenlee EB, Amick JR, Ligon GF, Lillquist JS, Natoli EJ, Hadari Y, Alvarado D, Schlessinger J. Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 13225-13230. PMID: 26460020, PMCID: PMC4629334, DOI: 10.1073/pnas.1518361112.Peer-Reviewed Original ResearchConceptsAllosteric mechanismExtracellular domainUnique allosteric mechanismFormation of heterodimersReceptor tyrosine kinasesEGF receptor familyTyrosine kinase domainStructure-based designPseudo-kinaseKinase domainLigand-dependent mechanismInactive conformationTyrosine kinaseInactive configurationReceptor familyFamily activationErbB3 activationErbB3KinaseErbB2ErbB4Family membersDomainActivationHeterodimerization
2023
Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention
Krimmer S, Bertoletti N, Suzuki Y, Katic L, Mohanty J, Shu S, Lee S, Lax I, Mi W, Schlessinger J. Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2300054120. PMID: 36943885, PMCID: PMC10068818, DOI: 10.1073/pnas.2300054120.Peer-Reviewed Original ResearchConceptsOncogenic KIT mutantsStem cell factorKIT mutantsHomotypic contactsCryo-EM analysisUnexpected structural plasticityLigand stem cell factorElectron microscopy structural analysisReceptor tyrosine kinase KITOncogenic mutantsHematopoietic stem cellsKIT dimerizationTyrosine kinase KITD5 regionPlasma membraneMutational analysisMutantsExtracellular domainGerm cellsHuman cancersSomatic gainCell factorStructural plasticityStem cellsKinase KIT
2020
FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho
Suzuki Y, Kuzina E, An SJ, Tome F, Mohanty J, Li W, Lee S, Liu Y, Lax I, Schlessinger J. FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 31800-31807. PMID: 33257569, PMCID: PMC7749347, DOI: 10.1073/pnas.2018554117.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCalcinosisCell MembraneFibroblast Growth Factor-23Fibroblast Growth FactorsGlucuronidaseHEK293 CellsHumansHyperostosis, Cortical, CongenitalHyperphosphatemiaImmunoglobulin Fc FragmentsKlotho ProteinsMutationOsteomalaciaProtein BindingProtein DomainsProtein MultimerizationRecombinant Fusion ProteinsRickets, HypophosphatemicConceptsFGF receptorsTotal internal reflection fluorescence microscopyChimeric receptor moleculesReflection fluorescence microscopyBinding sitesDisulfide bridge formationCritical metabolic processesMAPK responseCytoplasmic domainGrowth factor familyTerminal tailFactor familyKinase activationSimilar binding affinitiesExtracellular domainFGFR1 activationTandem repeatsMetabolic processesDisulfide bridgesCell surfaceDistinct ligandsCell membraneFluorescence microscopyDistinct high-affinity binding sitesPhosphate homeostasis