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Shyam Krishnakumar, PhD

Assistant Professor

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Research Summary

Understanding how complex information is reliably transmitted with millisecond precision and high fidelity from one nerve cell to another and how alterations in information processing lead to neurological disorders

Specialized Terms: Synaptic Transmission, Synaptic Regulation, Membrane Fusion, Neurological Disorders

Extensive Research Description

The release of neurotransmitters at the neuronal synapses is tightly controlled by changes in the presynaptic calcium concentration. To achieve this, synaptic vesicles (loaded with neurotransmitters) are already docked in the presynaptic membrane, ready to release the neurotransmitters when the signal (calcium ion) arrives. The protein machinery involved in this process are SNARE proteins, which catalyze the fusion of the vesicles; calcium sensors that synchronize the release of the neurotransmitter to the triggering calcium signal (Synaptotagmin isoforms) and regulatory proteins (Munc18/Munc13/Complexin ) that are involved in the organization of the release site. Our research is focused on elucidating how vesicular release protein machinery decodes the calcium signals and translate them into complex patterns of neurotransmitter release required for brain function.

The controlled release of neurotransmitters is central to information processing in the nervous system and is altered in many psychiatric and neurological disorders as is clear from well-established clinical benefits achieved by drugs that modulate neurotransmitter biochemistry and/or availability. So, we also aim to uncover the molecular and mechanistic basis for neurological disorders.

Our strategy is based on the systematic quantitative analysis of mutations both novel structure-based designer mutants as well as ‘experiments of nature’ - mutations associated with neurological disorders. We employ multidisciplinary biochemical, biophysical, and structural methods (with a specific focus on systematic biochemical reconstitution strategies) along with electrophysiology and high-resolution imaging in cultured neurons (in collaboration with Prof. Kirill Volynski, UCL Queen Square Institue of Neurology)

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Research Interests

Synaptic Transmission; Neurology; Neurosciences

Selected Publications

Native Planar Asymmetric Suspended Membrane for Single‐Molecule Investigations: Plasma Membrane on a ChipSundaram R, Bera M, Coleman J, Weerakkody J, Krishnakumar S, Ramakrishnan S. Native Planar Asymmetric Suspended Membrane for Single‐Molecule Investigations: Plasma Membrane on a Chip Small 2022, 18: e2205567. PMID: 36328714, DOI: 10.1002/smll.202205567.
Synaptotagmin rings as high-sensitivity regulators of synaptic vesicle docking and fusionZhu 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.
Molecular determinants of complexin clamping and activation functionBera 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.
Vesicle capture by membrane‐bound Munc13‐1 requires self‐assembly into discrete clustersLi F, Sundaram R, Gatta AT, Coleman J, Ramakrishnan S, Krishnakumar SS, Pincet F, Rothman JE. Vesicle capture by membrane‐bound Munc13‐1 requires self‐assembly into discrete clusters FEBS Letters 2021, 595: 2185-2196. PMID: 34227103, DOI: 10.1002/1873-3468.14157.
Symmetrical arrangement of proteins under release-ready vesicles in presynaptic terminalsRadhakrishnan A, Li X, Grushin K, Krishnakumar SS, Liu J, Rothman JE. Symmetrical arrangement of proteins under release-ready vesicles in presynaptic terminals Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2024029118. PMID: 33468631, PMCID: PMC7865176, DOI: 10.1073/pnas.2024029118.
Munc13 binds and recruits SNAP25 to chaperone SNARE complex assemblySundaram 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.
Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domainGruget C, Bello O, Coleman J, Krishnakumar SS, Perez E, Rothman JE, Pincet F, Donaldson SH. Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domain Scientific Reports 2020, 10: 18011. PMID: 33093513, PMCID: PMC7581758, DOI: 10.1038/s41598-020-74923-y.
Synergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosisRamakrishnan 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.
Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter releaseTagliatti 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.
Structural basis for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagminGrushin 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.
Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathyJepson JEC, Praschberger R, Krishnakumar SS. Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathy Neuroscience 2019, 420: 41-49. PMID: 30954670, DOI: 10.1016/j.neuroscience.2019.03.057.
Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human NeurodevelopmentSalpietro V, Malintan NT, Llano-Rivas I, Spaeth CG, Efthymiou S, Striano P, Vandrovcova J, Cutrupi MC, Chimenz R, David E, Di Rosa G, Marce-Grau A, Raspall-Chaure M, Martin-Hernandez E, Zara F, Minetti C, Study D, Group S, Salpietro V, Efthymiou S, Kriouile Y, Khorassani M, Aguennouz M, Karashova B, Avdjieva D, Kathom H, Tincheva R, Van Maldergem L, Nachbauer W, Boesch S, Arning L, Timmann D, Cormand B, Pérez-Dueñas B, Di Rosa G, Pironti E, Goraya J, Sultan T, Kirmani S, Ibrahim S, Jan F, Mine J, Banu S, Veggiotti P, Ferrari M, Verrotti A, Marseglia G, Savasta S, Garavaglia B, Scuderi C, Borgione E, Dipasquale V, Cutrupi M, Portaro S, Sanchez B, Pineda-Marfa’ M, Munell F, Macaya A, Boles R, Heimer G, Papacostas S, Manole A, Malintan N, Zanetti M, Hanna M, Rothman J, Kullmann D, Houlden H, Bello O, De Zorzi R, Fortuna S, Dauber A, Alkhawaja M, Sultan T, Mankad K, Vitobello A, Thomas Q, Mau-Them F, Faivre L, Martinez-Azorin F, Prada C, Macaya A, Kullmann D, Rothman J, Krishnakumar S, Houlden H. Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment American Journal Of Human Genetics 2019, 104: 721-730. PMID: 30929742, PMCID: PMC6451933, DOI: 10.1016/j.ajhg.2019.02.016.
Symmetrical organization of proteins under docked synaptic vesiclesLi 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.
Synaptotagmin oligomers are necessary and can be sufficient to form a Ca2+‐sensitive fusion clampRamakrishnan 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.
Using Nanodiscs to Probe Ca2+-Dependent Membrane Interaction of Synaptotagmin-1Stroeva E, Krishnakumar SS. Using Nanodiscs to Probe Ca2+-Dependent Membrane Interaction of Synaptotagmin-1 2018, 1860: 221-236. PMID: 30317508, DOI: 10.1007/978-1-4939-8760-3_14.
Synaptotagmin oligomerization is essential for calcium control of regulated exocytosisBello 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.
Synergistic control of neurotransmitter release by different members of the synaptotagmin familyVolynski 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.
Rearrangements 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.
PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex AssemblyColeman 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.
Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapsesMichalski 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.
Hypothesis – buttressed rings assemble, clamp, and release SNAREpins for synaptic transmissionRothman 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.
Two Disease-Causing SNAP-25B Mutations Selectively Impair SNARE C-terminal AssemblyRebane 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.
Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic IntegrityPraschberger R, Lowe SA, Malintan NT, Giachello CNG, Patel N, Houlden H, Kullmann DM, Baines RA, Usowicz MM, Krishnakumar SS, Hodge JJL, Rothman JE, Jepson JEC. Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity Cell Reports 2017, 21: 97-109. PMID: 28978487, PMCID: PMC5640804, DOI: 10.1016/j.celrep.2017.09.004.
Circular oligomerization is an intrinsic property of synaptotagminWang J, Li F, Bello OD, Sindelar CV, Pincet F, Krishnakumar SS, Rothman JE. Circular oligomerization is an intrinsic property of synaptotagmin ELife 2017, 6: e27441. PMID: 28850328, PMCID: PMC5576491, DOI: 10.7554/elife.27441.
Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndromeSalpietro 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.
Dilation of fusion pores by crowding of SNARE proteinsWu 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.
Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarizationVivekananda 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.
Ring-like oligomers of Synaptotagmins and related C2 domain proteinsZanetti 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.
Nanodisc-cell fusion: control of fusion pore nucleation and lifetimes by SNARE protein transmembrane domainsWu 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.
Using ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion PoresBello 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.
Re-visiting the trans insertion model for complexin clampingKrishnakumar 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.
Control of Fusion Pore Nucleation and Dynamics by SNARE Protein Transmembrane DomainsWu Z, Auclair S, Bello O, Vennekate W, Krishnakumar S, Karatekin E. Control of Fusion Pore Nucleation and Dynamics by SNARE Protein Transmembrane Domains Biophysical Journal 2015, 108: 408a. DOI: 10.1016/j.bpj.2014.11.2238.
Calcium sensitive ring-like oligomers formed by synaptotagminWang 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.
Conformational Dynamics of Calcium-Triggered Activation of Fusion by SynaptotagminKrishnakumar 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.
A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusionKrishnakumar SS, Radoff DT, Kümmel D, Giraudo CG, Li F, Khandan L, Baguley SW, Coleman J, Reinisch KM, Pincet F, Rothman JE. A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion Nature Structural & Molecular Biology 2011, 18: 934-940. PMID: 21785412, PMCID: PMC3668341, DOI: 10.1038/nsmb.2103.
Complexin cross-links prefusion SNAREs into a zigzag arrayKümmel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG, Pincet F, Rothman JE, Reinisch KM. Complexin cross-links prefusion SNAREs into a zigzag array Nature Structural & Molecular Biology 2011, 18: 927-933. PMID: 21785414, PMCID: PMC3410656, DOI: 10.1038/nsmb.2101.
The Effect of Hydrophilic Substitutions and Anionic Lipids upon the Transverse Positioning of the Transmembrane Helix of the ErbB2 (neu) Protein Incorporated into Model Membrane VesiclesShahidullah K, Krishnakumar SS, London E. The Effect of Hydrophilic Substitutions and Anionic Lipids upon the Transverse Positioning of the Transmembrane Helix of the ErbB2 (neu) Protein Incorporated into Model Membrane Vesicles Journal Of Molecular Biology 2009, 396: 209-220. PMID: 19931543, PMCID: PMC2821092, DOI: 10.1016/j.jmb.2009.11.037.
The Control of Transmembrane Helix Transverse Position in Membranes by Hydrophilic ResiduesKrishnakumar SS, London E. The Control of Transmembrane Helix Transverse Position in Membranes by Hydrophilic Residues Journal Of Molecular Biology 2007, 374: 1251-1269. PMID: 17997412, PMCID: PMC2175128, DOI: 10.1016/j.jmb.2007.10.032.
Effect of Sequence Hydrophobicity and Bilayer Width upon the Minimum Length Required for the Formation of Transmembrane Helices in MembranesKrishnakumar SS, London E. Effect of Sequence Hydrophobicity and Bilayer Width upon the Minimum Length Required for the Formation of Transmembrane Helices in Membranes Journal Of Molecular Biology 2007, 374: 671-687. PMID: 17950311, PMCID: PMC2121326, DOI: 10.1016/j.jmb.2007.09.037.
Membrane Topography of the Hydrophobic Anchor Sequence of Poliovirus 3A and 3AB Proteins and the Functional Effect of 3A/3AB Membrane Association upon RNA Replication †Fujita K, Krishnakumar SS, Franco D, Paul AV, London E, Wimmer E. Membrane Topography of the Hydrophobic Anchor Sequence of Poliovirus 3A and 3AB Proteins and the Functional Effect of 3A/3AB Membrane Association upon RNA Replication † Biochemistry 2007, 46: 5185-5199. PMID: 17417822, PMCID: PMC2519882, DOI: 10.1021/bi6024758.
Multiple‐probe analysis of folding and unfolding pathways of human serum albuminSantra MK, Banerjee A, Krishnakumar SS, Rahaman O, Panda D. Multiple‐probe analysis of folding and unfolding pathways of human serum albumin The FEBS Journal 2004, 271: 1789-1797. PMID: 15096218, DOI: 10.1111/j.1432-1033.2004.04096.x.
Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor DimerSeubert 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.
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.
Spatial Relationship between the Prodan Site, Trp-214, and Cys-34 Residues in Human Serum Albumin and Loss of Structure through Incremental Unfolding †Krishnakumar SS, Panda D. Spatial Relationship between the Prodan Site, Trp-214, and Cys-34 Residues in Human Serum Albumin and Loss of Structure through Incremental Unfolding † Biochemistry 2002, 41: 7443-7452. PMID: 12044178, DOI: 10.1021/bi025699v.

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Shyam Krishnakumar, PhD

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