2023
The release of inhibition model reproduces kinetics and plasticity of neurotransmitter release in central synapses
Norman C, Krishnakumar S, Timofeeva Y, Volynski K. The release of inhibition model reproduces kinetics and plasticity of neurotransmitter release in central synapses. Communications Biology 2023, 6: 1091. PMID: 37891212, PMCID: PMC10611806, DOI: 10.1038/s42003-023-05445-2.Peer-Reviewed Original ResearchConceptsFusion clampSV exocytosisSynaptic vesiclesNeurotransmitter releaseSNARE complexSNARE proteinsSV fusionPhysiological timescalesSynaptotagmin-1Synergistic regulationMolecular biochemistryComplete assemblyPresynaptic proteinsSynaptotagmin-7Molecular architectureCalcium bindingExocytosisDual bindingProteinCentral synapsesBindingPlasticitySynaptotagminSnareVesicles
2022
Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion
Zhu J, McDargh ZA, Li F, Krishnakumar SS, Rothman JE, O’Shaughnessy B. Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusion. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2208337119. PMID: 36103579, PMCID: PMC9499556, DOI: 10.1073/pnas.2208337119.Peer-Reviewed Original ResearchConceptsVesicle dockingPlasma membrane domainsSynaptic vesiclesCalcium sensor synaptotagminSynaptic vesicle dockingInhibitor of fusionFusion clampSensor synaptotagminMembrane domainsTrigger fusionPlasma membraneC2AB domainAnionic phospholipid bilayersNeuronal synapsesMembrane compositionPhospholipid monolayersATP levelsVesiclesExocytotic releaseDockingPhospholipid bilayersMolecular determinants of complexin clamping and activation function
Bera M, Ramakrishnan S, Coleman J, Krishnakumar SS, Rothman JE. Molecular determinants of complexin clamping and activation function. ELife 2022, 11: e71938. PMID: 35442188, PMCID: PMC9020821, DOI: 10.7554/elife.71938.Peer-Reviewed Original ResearchConceptsSynaptotagmin-1Single-vesicle fusionAccessory helixFusion clampHelical domainMolecular detailsComplexinMutational analysisVesicle releaseFusion kineticsMolecular determinantsSpecific interactionsInhibitory functionProbability of fusionRapid CaSNAREpinsAssembly processFusionClamping functionDomainHelixVesiclesFunctionMembraneInteraction
2020
Synergistic 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 roleFusionExocytosisMachineryProteinBindsMechanism
2019
Structural basis for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagmin
Grushin K, Wang J, Coleman J, Rothman JE, Sindelar CV, Krishnakumar SS. Structural basis for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagmin. Nature Communications 2019, 10: 2413. PMID: 31160571, PMCID: PMC6546687, DOI: 10.1038/s41467-019-10391-x.Peer-Reviewed Original ResearchConceptsCryo-electron microscopy structureActivation of SNAREsDependent membrane interactionsAnionic lipid headgroupsFusion clampActivator functionSNARE bundleSNARE proteinsMicroscopy structureC2B domainStructural basisSynaptotagmin-1SNAREpinsAliphatic loopsMembrane interactionsComplete assemblyLipid headgroupsLipid membranesNeurotransmitter releaseMembraneKey determinantSynaptotagminSyt1Calcium influxPartial insertionSymmetrical organization of proteins under docked synaptic vesicles
Li X, Radhakrishnan A, Grushin K, Kasula R, Chaudhuri A, Gomathinayagam S, Krishnakumar SS, Liu J, Rothman JE. Symmetrical organization of proteins under docked synaptic vesicles. FEBS Letters 2019, 593: 144-153. PMID: 30561792, PMCID: PMC6353562, DOI: 10.1002/1873-3468.13316.Peer-Reviewed Original ResearchConceptsCryo-electron tomography analysisSymmetrical organizationCalcium-regulated exocytosisMunc18 proteinsProtein machineryFusion machinerySingle SNAREpinCircular oligomersMutational analysisRadial positioningSynaptic vesiclesRelease machineryMachinerySynaptotagminProteinRing hypothesisVesiclesObserved arrangementUnderlying mechanismSNAREpinsComplexinNerve growthExocytosisGrowthSynaptotagmin oligomers are necessary and can be sufficient to form a Ca2+‐sensitive fusion clamp
Ramakrishnan S, Bera M, Coleman J, Krishnakumar SS, Pincet F, Rothman JE. Synaptotagmin oligomers are necessary and can be sufficient to form a Ca2+‐sensitive fusion clamp. FEBS Letters 2019, 593: 154-162. PMID: 30570144, PMCID: PMC6349546, DOI: 10.1002/1873-3468.13317.Peer-Reviewed Original Research
2018
Using Nanodiscs to Probe Ca2+-Dependent Membrane Interaction of Synaptotagmin-1
Stroeva E, Krishnakumar SS. Using Nanodiscs to Probe Ca2+-Dependent Membrane Interaction of Synaptotagmin-1. Methods In Molecular Biology 2018, 1860: 221-236. PMID: 30317508, DOI: 10.1007/978-1-4939-8760-3_14.BooksSynaptotagmin oligomerization is essential for calcium control of regulated exocytosis
Bello OD, Jouannot O, Chaudhuri A, Stroeva E, Coleman J, Volynski KE, Rothman JE, Krishnakumar SS. Synaptotagmin oligomerization is essential for calcium control of regulated exocytosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e7624-e7631. PMID: 30038018, PMCID: PMC6094142, DOI: 10.1073/pnas.1808792115.Peer-Reviewed Original ResearchConceptsRegulated exocytosisFusion machineryC2 domain proteinsCore fusion machinerySingle vesicle exocytosisConstitutive exocytosisPrincipal CaVesicular releaseMolecular mechanismsSensitive oligomersExocytosisPheochromocytoma cellsSelective disruptionSpontaneous fusionCritical roleMachineryOligomerizationDirect activationCentral componentStructural featuresConsiderable insightCalcium controlPHluorinSyt1SYTSynergistic control of neurotransmitter release by different members of the synaptotagmin family
Volynski KE, Krishnakumar SS. Synergistic control of neurotransmitter release by different members of the synaptotagmin family. Current Opinion In Neurobiology 2018, 51: 154-162. PMID: 29886350, DOI: 10.1016/j.conb.2018.05.006.Peer-Reviewed Original ResearchRearrangements under confinement lead to increased binding energy of Synaptotagmin‐1 with anionic membranes in Mg2+ and Ca2+
Gruget C, Coleman J, Bello O, Krishnakumar SS, Perez E, Rothman JE, Pincet F, Donaldson SH. Rearrangements under confinement lead to increased binding energy of Synaptotagmin‐1 with anionic membranes in Mg2+ and Ca2+. FEBS Letters 2018, 592: 1497-1506. PMID: 29578584, DOI: 10.1002/1873-3468.13040.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 synapses
2016
Ring-like oligomers of Synaptotagmins and related C2 domain proteins
Zanetti MN, Bello OD, Wang J, Coleman J, Cai Y, Sindelar CV, Rothman JE, Krishnakumar SS. Ring-like oligomers of Synaptotagmins and related C2 domain proteins. ELife 2016, 5: e17262. PMID: 27434670, PMCID: PMC4977156, DOI: 10.7554/elife.17262.Peer-Reviewed Original ResearchNanodisc-cell fusion: control of fusion pore nucleation and lifetimes by SNARE protein transmembrane domains
Wu Z, Auclair SM, Bello O, Vennekate W, Dudzinski NR, Krishnakumar SS, Karatekin E. Nanodisc-cell fusion: control of fusion pore nucleation and lifetimes by SNARE protein transmembrane domains. Scientific Reports 2016, 6: 27287. PMID: 27264104, PMCID: PMC4893671, DOI: 10.1038/srep27287.Peer-Reviewed Original ResearchConceptsFusion poreTransmembrane domainPore dynamicsProtein transmembrane domainNeurotransmitter-filled vesiclesT-SNAREsPlasma membraneRecycling kineticsPore lifetimePore currentsFlickering poresPore stabilityMultiple timesZipperingNanodiscsDomainProteinVesiclesMembraneCellsAssaysCognatesPore propertiesPoresUsing ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion Pores
Bello OD, Auclair SM, Rothman JE, Krishnakumar SS. Using ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion Pores. Langmuir 2016, 32: 3015-3023. PMID: 26972604, PMCID: PMC4946868, DOI: 10.1021/acs.langmuir.6b00245.Peer-Reviewed Original ResearchMeSH KeywordsApolipoproteins ECalciumCholesterolDextransDimyristoylphosphatidylcholineDithioniteFluorescent DyesLiposomesMembrane FusionNanoparticlesParticle SizePhosphatidylcholinesPhosphatidylethanolaminesPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhosphatidylserinesSynaptosomal-Associated Protein 25Syntaxin 1Vesicle-Associated Membrane Protein 2
2014
Calcium sensitive ring-like oligomers formed by synaptotagmin
Wang J, Bello O, Auclair SM, Wang J, Coleman J, Pincet F, Krishnakumar SS, Sindelar CV, Rothman JE. Calcium sensitive ring-like oligomers formed by synaptotagmin. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 13966-13971. PMID: 25201968, PMCID: PMC4183308, DOI: 10.1073/pnas.1415849111.Peer-Reviewed Original ResearchConceptsSynaptic vesicle protein Synaptotagmin 1Cytosolic domainSoluble N-ethylmaleimide-sensitive factorN-ethylmaleimide-sensitive factorMembrane fusion machineryReceptor complex assemblyRing-like oligomersFusion machineryC2 domainComplex assemblySynaptotagmin-1Helical reconstructionFusion proceedsNovel mechanismStructural mechanismsLipid monolayersNeurotransmitter releaseAbsence of calciumPhysiological concentrationsRing formationPresence of calciumFree calcium ionsSynaptotagminCalcium influxCircular arrangement
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
2002
Glutamate-induced Assembly of Bacterial Cell Division Protein FtsZ*
Beuria TK, Krishnakumar SS, Sahar S, Singh N, Gupta K, Meshram M, Panda D. Glutamate-induced Assembly of Bacterial Cell Division Protein FtsZ*. Journal Of Biological Chemistry 2002, 278: 3735-3741. PMID: 12446699, DOI: 10.1074/jbc.m205760200.Peer-Reviewed Original Research