Titus Boggon, PhD
Professor of PharmacologyCards
About
Research
Publications
2025
Structural basis for MEKK2 dimerization and substrate recognition
Vish K, Huet-Calderwood C, Ha B, Calderwood D, Boggon T. Structural basis for MEKK2 dimerization and substrate recognition. Nature Communications 2025 PMID: 41318559, DOI: 10.1038/s41467-025-66884-5.Peer-Reviewed Original ResearchMAP3KMitogen-activated protein kinase kinase kinaseC-terminal regionSubstrate recognitionSubstrate targetingDomain interactionsKinase domainMEKK2Kinase kinaseSmall molecule inhibitorsStructural basisMEK5MKK6Diverse substratesMolecule inhibitorsMEKK3MAP3PhosphorylationK substrateActivation segmentImmune systemMAP3KsAutophosphorylationSubstrateDimerOptimized conditions for GTP loading of Ras
Vish K, Paul M, Rollins A, Boggon T. Optimized conditions for GTP loading of Ras. Journal Of Biological Chemistry 2025, 301: 110923. PMID: 41207625, PMCID: PMC12719659, DOI: 10.1016/j.jbc.2025.110923.Peer-Reviewed Original ResearchGTP loading of RasGTP-loaded stateSmall GTPasesH-RasGTP loadingIntrinsic GTP hydrolysisBiochemical studiesNucleotide-bound stateExchange of GDPMyriad cellular processesDownstream Signaling PathwaysNucleotide compositionAnion-exchange chromatographyGTP hydrolysisNucleotide exchangeExcess nucleotideIn vitro exchangeCellular processesCancer mutationsGTPaseGTPSignaling pathwayNucleotideIsoform identityNucleotide contentNickel Binding to the c-Src SH3 Domain Facilitates Crystallization
Calicdan X, Fisher O, Ha B, Boggon T, Stiegler A. Nickel Binding to the c-Src SH3 Domain Facilitates Crystallization. Protein And Peptide Letters 2025, 32: 679-692. PMID: 41088944, PMCID: PMC12582252, DOI: 10.2174/0109298665417324250929120040.Peer-Reviewed Original ResearchC-Src SH3 domainSH3 domainC-SrcCrystal structureCrystallization bufferPseudo-twofold rotation axisX-ray crystal structureSpace group H32Nickel bindingSrc SH3 domainAmino acid sequenceCrystal formsUnique crystal structureSurface-exposed histidine residuesOrdered water moleculesCrystal lattice contactsMultiple crystal formsAmino-terminal copperMetal-mediated crystallizationCrystal packingAtomic-level informationAcid sequenceWater moleculesNickel coordinationLattice contactsMichaelis-Menten kinetics of RasGAP proteins by a rapid fluorescence-based assay
Paul M, Vish K, Boggon T. Michaelis-Menten kinetics of RasGAP proteins by a rapid fluorescence-based assay. Methods 2025, 244: 108-117. PMID: 40930400, PMCID: PMC12453608, DOI: 10.1016/j.ymeth.2025.09.003.Peer-Reviewed Original ResearchGTPase-activating proteinSmall GTPasesMichaelis-Menten kinetic profilesAction of GTPase-activating proteinsGTPase-activating proteins proteinMichaelis-Menten kineticsPeriplasmic phosphate binding proteinGTP-loaded stateRas small GTPasesSmall GTPase activityPhosphate binding proteinFluorescence-based assayMichaelis-MentenGTP hydrolysisGTPase activityProteins cycleRasGAP proteinCellular processesGDP-loadedSensor proteinsActivator proteinGTPaseH-RasBinding proteinProteinSHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis
Perla S, Stiegler A, Yi J, Enyenihi L, Zhang L, Riaz M, An E, Qyang Y, Boggon T, Bennett A. SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2503631122. PMID: 40854126, PMCID: PMC12415285, DOI: 10.1073/pnas.2503631122.Peer-Reviewed Original ResearchConceptsKnock-in mutationSH2 domainGenetic variantsSH2 domains of SHP2Iroquois homeoboxBinding to SHP2NSML miceProtein tyrosine phosphataseHypertrophic cardiomyopathyExpression levelsPhosphorylation-deficientProtein expressionCellular SrcTranscription factor 3Tyrosine phosphataseSHP2Protein zeroRare autosomal dominant disorderLow-dose dasatinibAutosomal dominant disorderPostnatal cardiac growthExpression of Irx3Signaling AxisIRX3Factor 3Complement factor I deficiency–associated neuroinflammatory disease among Old Order Amish
Reid W, Baas L, Stiegler A, Boggon T, Kreiger P, Sullivan K, Behrens E, Kandula V, van den Heuvel L, Brigatti K, Carson V, Romberg N. Complement factor I deficiency–associated neuroinflammatory disease among Old Order Amish. The Journal Of Allergy And Clinical Immunology 2025, 156: 835-841. PMID: 40602690, DOI: 10.1016/j.jaci.2025.06.021.Peer-Reviewed Original ResearchConceptsCerebral spinal fluid pleocytosisSpinal fluid pleocytosisInborn disorderClinical response to eculizumabSpine magnetic resonance imagingResponse to eculizumabSingle-center cohortAcute disseminated encephalomyelitisOld Order Amish populationMagnetic resonance imagingTransverse myelitisDisseminated encephalomyelitisFemale predominanceHomozygous patientsLeukocyte frequenciesLive birthsAseptic meningoencephalitisCytokine concentrationsDiagnostic considerationsAmish populationComplement consumptionPatient samplesClinical laboratoriesComplement regulatorsNeuroinflammatory diseasesNovel heterozygous SPI1c.538C>T p.(Leu180Phe) variant causes PU.1 haploinsufficiency leading to agammaglobulinemia
Daddali R, Kettunen K, Turunen T, Knox A, Laine P, Chowdhury I, Vänttinen M, Mamia N, Stiegler A, Boggon T, Kere J, Romberg N, Seppänen M, Varjosalo M, Martelius T, Grönholm J. Novel heterozygous SPI1c.538C>T p.(Leu180Phe) variant causes PU.1 haploinsufficiency leading to agammaglobulinemia. Clinical Immunology 2025, 277: 110503. PMID: 40294836, DOI: 10.1016/j.clim.2025.110503.Peer-Reviewed Original ResearchConceptsDendritic cell countHeterozygous loss-of-function variantsLoss-of-function variantsCentrosome-associated proteinsFamily transcription factorsEts family transcription factorGene expression patternsAssociated with B cell developmentHematopoietic cell fatePDC countsB cell developmentCell countDisrupts gene expression patternsB-cell countsCell fateCarrier sisterSevere bacterial infectionsTranscription factorsIsolated IgA deficiencyFinnish familiesExpression patternsIn vitro studiesIgA deficiencyVariable penetranceIndex patientCancer hotspot mutations rewire ERK2 specificity by selective exclusion of docking interactions
Robles J, Stiegler A, Boggon T, Turk B. Cancer hotspot mutations rewire ERK2 specificity by selective exclusion of docking interactions. Journal Of Biological Chemistry 2025, 301: 108348. PMID: 40015635, PMCID: PMC11982978, DOI: 10.1016/j.jbc.2025.108348.Peer-Reviewed Original ResearchShort linear motifsCancer hotspot mutationsLinear motifsERK substratesYeast two-hybrid libraryHotspot mutationsTwo-hybrid libraryCancer-associated mutantsDocking interactionsWild-type ERK2Cancer-associated mutationsDocking motifBinding sequenceKinase ERK2Co-crystal structureMutant formsERK2 mutantsDisordered regionsERK2MotifStructural rationalePeptide bindingMutationsWT kinasePeptide fragmentsThe C2 domain augments Ras GTPase-activating protein catalytic activity
Paul M, Chen D, Vish K, Lartey N, Hughes E, Freeman Z, Saunders T, Stiegler A, King P, Boggon T. The C2 domain augments Ras GTPase-activating protein catalytic activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418433122. PMID: 39899710, PMCID: PMC11831179, DOI: 10.1073/pnas.2418433122.Peer-Reviewed Original ResearchConceptsGTPase-activating proteinC2 domainActivity of GTPase-activating proteinGTPase-activating protein domainProtein catalytic activityDomain in vitroAllosteric lobeRas GTPasesSequence conservationGTPase activityAlphaFold modelsRasGAPSignaling defectsRasMutationsCatalytic activityConstitutive disruptionCatalytic advantageGTPaseAlphaFoldDomainGenesSynGAPProteinSequence
2024
Regulation and signaling of the LIM domain kinases
Casanova‐Sepúlveda G, Boggon T. Regulation and signaling of the LIM domain kinases. BioEssays 2024, 47: e2400184. PMID: 39361252, PMCID: PMC11663136, DOI: 10.1002/bies.202400184.Peer-Reviewed Original ResearchLIM domain kinaseDownstream of Rho GTPasesCofilin/actin depolymerizing factorActin cytoskeleton regulationIntra-molecular mechanismFilament severingDepolymerizing factorRho GTPasesActin depolymerizationCytoskeleton regulationRegulation mechanismKinaseLIMProteinRegulationGTPaseLIMK2LIMK1ActinEnzymeHuman healthSignalDepolymerizationCascadeMechanism
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New Haven, CT 06510