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
Molecular 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 insertionSynaptotagmin 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 ResearchSymmetrical 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 growthExocytosisGrowth
2018
PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly
Coleman J, Jouannot O, Ramakrishnan SK, Zanetti MN, Wang J, Salpietro V, Houlden H, Rothman JE, Krishnakumar SS. PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly. Cell Reports 2018, 22: 820-831. PMID: 29346777, PMCID: PMC5792450, DOI: 10.1016/j.celrep.2017.12.056.Peer-Reviewed Original ResearchConceptsProline-rich transmembrane protein 2SNARE complex assemblyComplex assemblyTrans-SNARE complex assemblyTerminal proline-rich domainSynaptic SNARE proteinsProline-rich domainParoxysmal neurological disordersSynaptic vesicle primingLive-cell imagingTransmembrane protein 2Synaptic fusionSNARE proteinsVesicle primingSingle exocytotic eventsBiophysical analysisFusion assaysMolecular mechanismsFunction mutationsPhysiological roleExocytotic eventsPre-synaptic terminalsPC12 cellsProtein 2Single vesicles
2017
Hypothesis – buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission
Rothman JE, Krishnakumar SS, Grushin K, Pincet F. Hypothesis – buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission. FEBS Letters 2017, 591: 3459-3480. PMID: 28983915, PMCID: PMC5698743, DOI: 10.1002/1873-3468.12874.Peer-Reviewed Original ResearchDilation of fusion pores by crowding of SNARE proteins
Wu Z, Bello OD, Thiyagarajan S, Auclair SM, Vennekate W, Krishnakumar SS, O'Shaughnessy B, Karatekin E. Dilation of fusion pores by crowding of SNARE proteins. ELife 2017, 6: e22964. PMID: 28346138, PMCID: PMC5404929, DOI: 10.7554/elife.22964.Peer-Reviewed Original Research
2016
Nanodisc-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 propertiesPores
2015
Re-visiting the trans insertion model for complexin clamping
Krishnakumar SS, Li F, Coleman J, Schauder CM, Kümmel D, Pincet F, Rothman JE, Reinisch KM. Re-visiting the trans insertion model for complexin clamping. ELife 2015, 4: e04463. PMID: 25831964, PMCID: PMC4384536, DOI: 10.7554/elife.04463.Peer-Reviewed Original ResearchAdaptor Proteins, Vesicular TransportAlgorithmsAnimalsCalorimetryCircular DichroismEntropyFluorescence Resonance Energy TransferHumansKineticsMembrane FusionModels, NeurologicalMutationNerve Tissue ProteinsNeuronsProtein BindingSignal TransductionSNARE ProteinsSynaptic TransmissionSynaptotagminsVesicle-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 ResearchMeSH KeywordsCalciumHumansLipid BilayersMultiprotein ComplexesProtein Structure, TertiarySNARE ProteinsSynaptotagmin IConceptsSynaptic 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