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)
Coauthors
Research Interests
Synaptic Transmission; Neurology; Neurosciences
Selected Publications
- Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly.Kalyana Sundaram RV, 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 2021, 595:297-309.
- Symmetrical arrangement of proteins under release-ready vesicles in presynaptic terminals.Radhakrishnan 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.
- Vesicle capture by membrane-bound Munc13-1 requires self-assembly into discrete clusters.Li F, Kalyana Sundaram V, 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.
- Synaptotagmin 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.
- 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.
- Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domain.Gruget 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.
- 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 (Clifton, N.J.) 2019, 1860:221-236.
- Symmetrical 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.
- Synaptotagmin 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.
- Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.Salpietro 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, Bello OD, De Zorzi R, Fortuna S, Dauber A, Alkhawaja M, Sultan T, Mankad K, Vitobello A, Thomas Q, Mau-Them FT, Faivre L, Martinez-Azorin F, Prada CE, Macaya A, Kullmann DM, Rothman JE, Krishnakumar SS, 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.
- 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.
- Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathy.Jepson JEC, Praschberger R, Krishnakumar SS. Mechanisms of Neurological Dysfunction in GOSR2 Progressive Myoclonus Epilepsy, a Golgi SNAREopathy. Neuroscience 2019, 420:41-49.
- 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.
- 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.
- Two 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 2018, 430:479-490.
- Synaptotagmin 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.
- Synergistic 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.
- Homozygous 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, 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.
- Kv1.1 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.
- Dilation 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.
- Correction: 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. Correction: Re-visiting the trans insertion model for complexin clamping. ELife 2017, 6.
- Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity.Praschberger 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.
- 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.
- Circular oligomerization is an intrinsic property of synaptotagmin.Wang J, Li F, Bello OD, Sindelar CV, Pincet F, Krishnakumar SS, Rothman JE. Circular oligomerization is an intrinsic property of synaptotagmin. ELife 2017, 6.
- 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, Boutet 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.
- Using 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 : The ACS Journal Of Surfaces And Colloids 2016, 32:3015-23.
- 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.
- 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.
- 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.
- 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, 111:13966-71.
- 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, 105:2507-16.
- A conformational switch in complexin is required for synaptotagmin to trigger synaptic fusion.Krishnakumar 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, 18:934-40.
- Complexin cross-links prefusion SNAREs into a zigzag array.Kümmel 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, 18:927-33.
- 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.Shahidullah 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 2010, 396:209-20.
- 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, 46:5185-99.
- Effect of sequence hydrophobicity and bilayer width upon the minimum length required for the formation of transmembrane helices in membranes.Krishnakumar 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, 374:671-87.
- The control of transmembrane helix transverse position in membranes by hydrophilic residues.Krishnakumar SS, London E. The control of transmembrane helix transverse position in membranes by hydrophilic residues. Journal Of Molecular Biology 2007, 374:1251-69.
- Multiple-probe analysis of folding and unfolding pathways of human serum albumin. Evidence for a framework mechanism of folding.Santra MK, Banerjee A, Krishnakumar SS, Rahaman O, Panda D. Multiple-probe analysis of folding and unfolding pathways of human serum albumin. Evidence for a framework mechanism of folding. European Journal Of Biochemistry / FEBS 2004, 271:1789-97.
- 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, 12:1239-50.
- 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. The Journal Of Biological Chemistry 2003, 278:3735-41.
- 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, 41:7443-52.