Moitrayee Bhattacharyya, PhD
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Overview
With the advances in genomic technologies and structural tools, we are increasingly learning about the identity and structural organizations of individual proteins that play a critical role in cellular signal transduction. These proteins usually work in an organized, interdependent macromolecular network. The next set of challenges are to: (1) understand the proteins in this network in terms of their composition, posttranslational modifications (PTMs) and stoichiometry with spatiotemporal resolution, (2) understand the regulatory role of kinases and phosphatases within these networks, (3) understand the role of lipid microenvironment in dictating the assembly and function of proteins, (4) determine how physico-chemical perturbations, such as oxidative/chemotoxic stress and ultimately aging, affect proteins in this network, and (5) probe how proteins in this molecular network are altered in disease states. The Bhattacharyya Lab aims to answer some of these outstanding molecular questions in the context of learning and memory, and cognitive impairments in Down Syndrome.
I. kinase signaling in the brain
How we learn, how our memories form, and how under certain neuropathological conditions such faculties are compromised? Protein kinases orchestrate the regulation of signaling pathways that are pivotal to cellular development and function. We aim to achieve a molecular understanding of the regulation and activation of kinases that are critical for learning, memory and synaptic plasticity. This includes (a) CaMKII, one of the most abundant protein kinases in neurons, (b) Dyrk1a, whose overexpression in trisomy 21 (Down Syndrome) leads to severe cognitive impairments, and (c) Dyrk3, a key regulator of cellular phase separation. We plan to address these questions using a multidisciplinary approach, combining structural biology and biophysics, single-molecule microscopy, and native mass spectrometry with computational techniques (Fig. 1). Our work will uncover how these kinases are moderated by layers of regulatory mechanisms and will help elucidate what goes awry under pathological conditions.
II. lipids matter in kinase signaling
How endogenous lipid microenvironment affect the assembly and signaling of receptor kinases? Lipids are known to modulate the activity of protein kinases. Alterations in the global membrane-lipid composition have been reported for neurological disorders, cancer, metabolic diseases and aging, where protein kinases play a critical role in disease development, perpetuation and prognosis. The goal of our lab is to obtain a high-resolution understanding of how such disease-associated changes in the global lipidome affect the lipid distribution in the immediate vicinity of receptor kinases, thereby affecting their ability to propagate signals. Using a novel spatial lipidomics technique, along with microscopy and biochemical approaches, our work will reveal how modifications in the lipid microenvironment around kinases (using Trk receptor tyrosine kinases as an example) potentially alter their signaling properties under physiological and pathological conditions (Fig. 2).
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Selected Publications
- Oligomeric organization of membrane proteins from native membranes at nanoscale spatial and single-molecule resolutionWalker G, Brown C, Ge X, Kumar S, Muzumdar M, Gupta K, Bhattacharyya M. Oligomeric organization of membrane proteins from native membranes at nanoscale spatial and single-molecule resolution. Nature Nanotechnology 2023, 19: 85-94. PMID: 38012273, DOI: 10.1038/s41565-023-01547-4.
- Oligomeric distribution of membrane proteins in native-membrane environment at nanoscale spatial and single-molecule resolutionWalker G, Brown C, Ge X, Gupta K, Muzumdar M, Bhattacharyya M. Oligomeric distribution of membrane proteins in native-membrane environment at nanoscale spatial and single-molecule resolution. Biophysical Journal 2023, 122: 457a. DOI: 10.1016/j.bpj.2022.11.2457.
- Deciphering the molecular organization of Get pathway chaperones through native top-down dissociation of multi-protein complexesGiska F, Mariappan M, Bhattacharyya M, Gupta K. Deciphering the molecular organization of Get pathway chaperones through native top-down dissociation of multi-protein complexes. Biophysical Journal 2022, 121: 333a. DOI: 10.1016/j.bpj.2021.11.1119.
- Breakage of the Oligomeric CaMKII Hub by the Regulatory Segment of the KinaseKarandur D, Bhattacharyya M, Xia Z, Lee YK, Muratcioglu S, McAffee D, McSpadden E, Qiu B, Groves JT, Williams ER, Kuriyan J. Breakage of the Oligomeric CaMKII Hub by the Regulatory Segment of the Kinase. ELife 2020, 9: e57784. PMID: 32902386, PMCID: PMC7538161, DOI: 10.7554/elife.57784.
- Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylationBhattacharyya M, Lee YK, Muratcioglu S, Qiu B, Nyayapati P, Schulman H, Groves JT, Kuriyan J. Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation. ELife 2020, 9: e53670. PMID: 32149607, PMCID: PMC7141811, DOI: 10.7554/elife.53670.
- Structural Insights into the Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII).Bhattacharyya M, Karandur D, Kuriyan J. Structural Insights into the Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII). Cold Spring Harbor Perspectives In Biology 2019, 12: a035147. PMID: 31653643, PMCID: PMC7263085, DOI: 10.1101/cshperspect.a035147.
- Deconstruction of the Ras switching cycle through saturation mutagenesisBandaru P, Shah NH, Bhattacharyya M, Barton JP, Kondo Y, Cofsky JC, Gee CL, Chakraborty AK, Kortemme T, Ranganathan R, Kuriyan J. Deconstruction of the Ras switching cycle through saturation mutagenesis. ELife 2017, 6: e27810. PMID: 28686159, PMCID: PMC5538825, DOI: 10.7554/elife.27810.
- Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase IIBhattacharyya M, Stratton MM, Going CC, McSpadden ED, Huang Y, Susa AC, Elleman A, Cao YM, Pappireddi N, Burkhardt P, Gee CL, Barros T, Schulman H, Williams ER, Kuriyan J. Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II. ELife 2016, 5: e13405. PMID: 26949248, PMCID: PMC4859805, DOI: 10.7554/elife.13405.
- Protein Structure and Function: Looking through the Network of Side-Chain Interactions.Bhattacharyya M, Ghosh S, Vishveshwara S. Protein Structure and Function: Looking through the Network of Side-Chain Interactions. Current Protein And Peptide Science 2016, 17: 4-25. PMID: 26412788, DOI: 10.2174/1389203716666150923105727.
- Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activityStratton M, Lee IH, Bhattacharyya M, Christensen SM, Chao LH, Schulman H, Groves JT, Kuriyan J. Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activity. ELife 2014, 3: e01610. PMID: 24473075, PMCID: PMC3901001, DOI: 10.7554/elife.01610.
- An automated approach to network features of protein structure ensemblesBhattacharyya M, Bhat CR, Vishveshwara S. An automated approach to network features of protein structure ensembles. Protein Science 2013, 22: 1399-1416. PMID: 23934896, PMCID: PMC3795498, DOI: 10.1002/pro.2333.
- Rapid mass spectrometric determination of disulfide connectivity in peptides and proteinsBhattacharyya M, Gupta K, Gowd KH, Balaram P. Rapid mass spectrometric determination of disulfide connectivity in peptides and proteins. Molecular Omics 2013, 9: 1340-1350. PMID: 23467691, DOI: 10.1039/c3mb25534d.
- Interaction Signatures Stabilizing the NAD(P)-Binding Rossmann Fold: A Structure Network ApproachBhattacharyya M, Upadhyay R, Vishveshwara S. Interaction Signatures Stabilizing the NAD(P)-Binding Rossmann Fold: A Structure Network Approach. PLOS ONE 2012, 7: e51676. PMID: 23284738, PMCID: PMC3524241, DOI: 10.1371/journal.pone.0051676.
- Probing the Allosteric Mechanism in Pyrrolysyl-tRNA Synthetase Using Energy-Weighted Network FormalismBhattacharyya M, Vishveshwara S. Probing the Allosteric Mechanism in Pyrrolysyl-tRNA Synthetase Using Energy-Weighted Network Formalism. Biochemistry 2011, 50: 6225-6236. PMID: 21650159, DOI: 10.1021/bi200306u.
- Quantum clustering and network analysis of MD simulation trajectories to probe the conformational ensembles of protein – ligand interactionsBhattacharyya M, Vishveshwara S. Quantum clustering and network analysis of MD simulation trajectories to probe the conformational ensembles of protein – ligand interactions. Molecular Omics 2011, 7: 2320-2330. PMID: 21617814, DOI: 10.1039/c1mb05038a.
- Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysisBhattacharyya M, Vishveshwara S. Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysis. BMC Molecular And Cell Biology 2010, 10: 27. PMID: 20704697, PMCID: PMC2929236, DOI: 10.1186/1472-6807-10-27.
- Recognition and Signaling in DNA Mismatch Repair: Interdomain Communication in T. Aquaticus Muts ProteinsPieniazek S, Bhattacharyya M, Vishveshwara S, Hingorani M, Beveridge D. Recognition and Signaling in DNA Mismatch Repair: Interdomain Communication in T. Aquaticus Muts Proteins. Biophysical Journal 2010, 98: 568a-569a. DOI: 10.1016/j.bpj.2009.12.3084.
- Allostery and conformational free energy changes in human tryptophanyl‐tRNA synthetase from essential dynamics and structure networksBhattacharyya M, Ghosh A, Hansia P, Vishveshwara S. Allostery and conformational free energy changes in human tryptophanyl‐tRNA synthetase from essential dynamics and structure networks. Proteins Structure Function And Bioinformatics 2009, 78: 506-517. PMID: 19768679, DOI: 10.1002/prot.22573.
- Functional correlation of bacterial LuxS with their quaternary associations: interface analysis of the structure networksBhattacharyya M, Vishveshwara S. Functional correlation of bacterial LuxS with their quaternary associations: interface analysis of the structure networks. BMC Molecular And Cell Biology 2009, 9: 8. PMID: 19243584, PMCID: PMC2656534, DOI: 10.1186/1472-6807-9-8.