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
2018
Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α)
Reshetnyak AV, Mohanty J, Tomé F, Puleo DE, Plotnikov AN, Ahmed M, Kaur N, Poliakov A, Cinnaiyan AM, Lax I, Schlessinger J. Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α). Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: 8340-8345. PMID: 30061385, PMCID: PMC6099872, DOI: 10.1073/pnas.1807881115.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAnaplastic Lymphoma KinaseAnimalsCytokinesHEK293 CellsHumansMiceNIH 3T3 CellsPC12 CellsProtein MultimerizationRatsReceptor Protein-Tyrosine KinasesConceptsLeukocyte tyrosine kinaseN-terminal variable regionDeletion mutantsVariable regionsDisulfide bridgesDetailed biochemical characterizationIntramolecular disulfide bridgesNIH 3T3 cellsSimilar tyrosine phosphorylationAnaplastic lymphoma kinaseReceptor-receptor interactionsMAP kinase responseTyrosine phosphorylationBiochemical characterizationTyrosine kinaseReceptor tyrosineNeuronal differentiationL6 cellsPhysiological roleMode of actionKinase responseCultured cellsPC12 cells
2014
The Strength and Cooperativity of KIT Ectodomain Contacts Determine Normal Ligand-Dependent Stimulation or Oncogenic Activation in Cancer
Reshetnyak AV, Opatowsky Y, Boggon TJ, Folta-Stogniew E, Tome F, Lax I, Schlessinger J. The Strength and Cooperativity of KIT Ectodomain Contacts Determine Normal Ligand-Dependent Stimulation or Oncogenic Activation in Cancer. Molecular Cell 2014, 57: 191-201. PMID: 25544564, PMCID: PMC4764128, DOI: 10.1016/j.molcel.2014.11.021.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBaculoviridaeBinding SitesCrystallography, X-RayEnzyme ActivationHumansLigandsMiceModels, MolecularMutationNeoplasmsNIH 3T3 CellsProtein BindingProtein FoldingProtein Interaction Domains and MotifsProtein MultimerizationProtein Structure, SecondaryProto-Oncogene Proteins c-kitRecombinant ProteinsSf9 CellsSpodopteraConceptsOncogenic KIT mutationsKIT mutationsGastrointestinal stromal tumorsAcute myeloid leukemiaKIT tyrosine kinase activitySomatic oncogenic mutationsInterstitial pacemaker cellsLigand-dependent stimulationReceptor tyrosine kinase KITStromal tumorsTyrosine kinase KITMyeloid leukemiaReceptor activationPacemaker cellsTyrosine kinase activityCancerKinase KITOncogenic mutationsHematopoietic cellsGerm cellsOncogenic activationActivationCellsReceptor moleculesMutationsStructure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers
Opatowsky Y, Lax I, Tomé F, Bleichert F, Unger VM, Schlessinger J. Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 1772-1777. PMID: 24449920, PMCID: PMC3918759, DOI: 10.1073/pnas.1323254111.Peer-Reviewed Original ResearchConceptsExtracellular regionConformational statesIg-like domainsReceptor tyrosine kinasesDifferent conformational statesTrans autophosphorylationTyrosine kinase domainMembrane-proximal Ig-like domainsTrans phosphorylationAutophosphorylation sitesDomain organizationKinase domainCytoplasmic regionHomotypic interactionsKinase activityReceptor dimersDimeric receptorTyrosine kinaseAsymmetric arrangementMolecular interactionsPrevalent conformationsCrystal structureAutophosphorylationDimersKinase