2020
Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly
Sundaram R, Jin H, Li F, Shu T, Coleman J, Yang J, Pincet F, Zhang Y, Rothman JE, Krishnakumar SS. Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly. FEBS Letters 2020, 595: 297-309. PMID: 33222163, PMCID: PMC8068094, DOI: 10.1002/1873-3468.14006.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesCloning, MolecularEscherichia coliGene ExpressionGenetic VectorsLipid BilayersLiposomesMiceModels, MolecularNerve Tissue ProteinsOptical TweezersPhosphatidylcholinesPhosphatidylethanolaminesPhosphatidylserinesPolyethylene GlycolsProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsRecombinant Fusion ProteinsSynaptosomal-Associated Protein 25Syntaxin 1Vesicle-Associated Membrane Protein 2ConceptsSNARE complex assemblyComplex assemblyMunc13-1 MUN domainDetailed structure-function analysisSNARE protein VAMP2Syntaxin 1/Structure-function analysisSynaptic vesicle fusionOptical tweezers studiesSNARE assemblySNARE motifMUN domainMunc18-1Syntaxin-1Munc13-1FRET spectroscopyLinker regionVesicle fusionDirect bindingPhospholipid bilayersPresynaptic membraneSNAP25AssemblyBindingRecruitsSynergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis
Ramakrishnan S, Bera M, Coleman J, Rothman JE, Krishnakumar SS. Synergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis. ELife 2020, 9: e54506. PMID: 32401194, PMCID: PMC7220375, DOI: 10.7554/elife.54506.Peer-Reviewed Original ResearchConceptsSynaptotagmin-1Vesicular fusion machinerySingle-vesicle fusionFusion of vesiclesSNARE complexFusion machineryNeuronal exocytosisOligomer bindsRegulatory proteinsVesicle fusionSNAREpinsSynchronous fusionSynaptic vesiclesNovel mechanismVesiclesComplexinKinetic delayPrimary interfaceSynergistic roleFusionExocytosisMachineryProteinBindsMechanismSynaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release
Tagliatti E, Bello OD, Mendonça PRF, Kotzadimitriou D, Nicholson E, Coleman J, Timofeeva Y, Rothman JE, Krishnakumar SS, Volynski KE. Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 3819-3827. PMID: 32015138, PMCID: PMC7035618, DOI: 10.1073/pnas.1920403117.Peer-Reviewed Original Research
2017
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses
Michalski N, Goutman JD, Auclair SM, de Monvel J, Tertrais M, Emptoz A, Parrin A, Nouaille S, Guillon M, Sachse M, Ciric D, Bahloul A, Hardelin JP, Sutton RB, Avan P, Krishnakumar SS, Rothman JE, Dulon D, Safieddine S, Petit C. Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses. ELife 2017, 6: e31013. PMID: 29111973, PMCID: PMC5700815, DOI: 10.7554/elife.31013.Peer-Reviewed Original ResearchConceptsVesicle fusionVesicle pool replenishmentIHC active zonesInner hair cellsPresynaptic plasma membraneSynaptic vesicle cycleMembrane capacitance measurementsRole of otoferlinAuditory brainstem response wavesTransmembrane proteinVesicle cycleSynaptic exocytosisPlasma membraneVoltage-gated CaHair cell ribbonC-domainSynaptic vesiclesOtoferlinSynaptic CaSensory cellsSynapse structureIntracellular CaNeurotransmitter releaseMutant miceRibbon synapsesTwo Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly
Rebane AA, Wang B, Ma L, Qu H, Coleman J, Krishnakumar S, Rothman JE, Zhang Y. Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal Assembly. Journal Of Molecular Biology 2017, 430: 479-490. PMID: 29056461, PMCID: PMC5805579, DOI: 10.1016/j.jmb.2017.10.012.Peer-Reviewed Original ResearchConceptsSoluble N-ethylmaleimide-sensitive factor attachment receptorSNARE assemblySynaptic exocytosisMembrane fusionSingle-molecule optical tweezersT-SNARE complexVesicle-associated SNAREsTarget plasma membraneC-terminal assemblyFour-helix bundleC-terminal regionSNARE complexPlasma membraneMolecular mechanismsZipperingMutationsNumerous diseasesAssembly energyNeurotransmitter releaseExocytosisAttachment receptorAssemblyNeurological disordersOptical tweezersComplexesHomozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome
Salpietro V, Lin W, Delle Vedove A, Storbeck M, Liu Y, Efthymiou S, Manole A, Wiethoff S, Ye Q, Saggar A, McElreavey K, Krishnakumar SS, Group S, Pitt M, Bello OD, Rothman JE, Basel‐Vanagaite L, Hubshman MW, Aharoni S, Manzur AY, Wirth B, Houlden H. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Annals Of Neurology 2017, 81: 597-603. PMID: 28253535, PMCID: PMC5413866, DOI: 10.1002/ana.24905.Peer-Reviewed Original ResearchConceptsPresynaptic congenital myasthenic syndromeCongenital myasthenic syndromePresynaptic impairmentMyasthenic syndromeLow compound muscle action potentialsNeuromuscular junctionCompound muscle action potentialPresynaptic neuromuscular junctionHomozygous mutationMuscle action potentialsAnn NeurolNMJ transmissionElectrodiagnostic examinationNeurophysiological featuresAction potentialsLew/Homozygous variantMRNA levelsSyndromeWhole exomeImpairmentVAMP1Kuwaiti familyNonsense mutationMutationsKv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization
Vivekananda U, Novak P, Bello OD, Korchev YE, Krishnakumar SS, Volynski KE, Kullmann DM. Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 2395-2400. PMID: 28193892, PMCID: PMC5338558, DOI: 10.1073/pnas.1608763114.Peer-Reviewed Original ResearchConceptsSomatic depolarizationPotassium channelsAction potentialsPresynaptic potassium channelsPrimary hippocampal culturesSubthreshold membrane potential fluctuationsHeterozygous mouse modelEpisodic ataxia type 1Distinct potassium channelsSubthreshold modulationAxon transectionSmall boutonsCalcium influxHippocampal culturesMouse modelSynaptic boutonsKv1.1 subunitsMembrane potential fluctuationsNeurotransmitter releaseIntact axonsType 1Genetic deletionAtaxia type 1Further prolongationPresynaptic spikes
2013
Conformational Dynamics of Calcium-Triggered Activation of Fusion by Synaptotagmin
Krishnakumar SS, Kümmel D, Jones SJ, Radoff DT, Reinisch KM, Rothman JE. Conformational Dynamics of Calcium-Triggered Activation of Fusion by Synaptotagmin. Biophysical Journal 2013, 105: 2507-2516. PMID: 24314081, PMCID: PMC3853086, DOI: 10.1016/j.bpj.2013.10.029.Peer-Reviewed Original Research
2003
Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor Dimer
Seubert N, Royer Y, Staerk J, Kubatzky KF, Moucadel V, Krishnakumar S, Smith SO, Constantinescu SN. Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor Dimer. Molecular Cell 2003, 12: 1239-1250. PMID: 14636581, DOI: 10.1016/s1097-2765(03)00389-7.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell LineDimerizationDNA-Binding ProteinsEnzyme ActivationErythroid Precursor CellsErythropoietinJanus Kinase 2MiceMilk ProteinsModels, MolecularMolecular Sequence DataProtein Structure, QuaternaryProtein Structure, SecondaryProtein Structure, TertiaryProtein-Tyrosine KinasesProto-Oncogene ProteinsReceptors, ErythropoietinRecombinant Fusion ProteinsSaccharomyces cerevisiae ProteinsSequence AlignmentSignal TransductionSTAT3 Transcription FactorSTAT5 Transcription FactorTrans-ActivatorsTranscription FactorsTranscription, GeneticViral Envelope Proteins