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519 results on '"Thaker, A. M."'

3. Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface

Author

Diwanji, Devan, Trenker, Raphael, Thaker, Tarjani M, Wang, Feng, Agard, David A, Verba, Kliment A, and Jura, Natalia

Subjects
Biochemistry and Cell Biology, Chemical Sciences, Biological Sciences, Breast Cancer, Cancer, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Generic health relevance, Allosteric Regulation, Antibodies, Monoclonal, Humanized, Binding Sites, Cryoelectron Microscopy, Humans, Immunoglobulin Fab Fragments, Models, Molecular, Mutation, Neuregulin-1, Oncogenes, Protein Multimerization, Protein Stability, Receptor, ErbB-2, Receptor, ErbB-3, Trastuzumab, Receptor, erbB-2, Receptor, erbB-3, General Science & Technology
Abstract

Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex1-3 upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2-HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2-HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2-HER3 and HER2(S310F)-HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)-HER3-NRG1β-trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2-HER3 heterodimer. The unique features of a singly liganded HER2-HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface.

Published
2021

4. A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection

Author

Ronk, Adam J., Lloyd, Nicole M., Zhang, Min, Atyeo, Caroline, Perrett, Hailee R., Mire, Chad E., Hastie, Kathryn M., Sanders, Rogier W., Brouwer, Philip J. M., Saphire, Erica Olmann, Ward, Andrew B., Ksiazek, Thomas G., Alvarez Moreno, Juan Carlos, Thaker, Harshwardhan M., Alter, Galit, Himansu, Sunny, Carfi, Andrea, and Bukreyev, Alexander

Published
2023
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7. Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.

Author

Ruiz, Karen, Thaker, Tarjani M, Agnew, Christopher, Miller-Vedam, Lakshmi, Trenker, Raphael, Herrera, Clara, Ingaramo, Maria, Toso, Daniel, Frost, Adam, and Jura, Natalia

Subjects
Animals, Mice, Cryoelectron Microscopy, Cell Death, Mitochondrial Membranes, Phosphoprotein Phosphatases, Polymerization, Mitophagy
Abstract

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.

Published
2019

10. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

Author

Pahuja, Kanika Bajaj, Nguyen, Thong T, Jaiswal, Bijay S, Prabhash, Kumar, Thaker, Tarjani M, Senger, Kate, Chaudhuri, Subhra, Kljavin, Noelyn M, Antony, Aju, Phalke, Sameer, Kumar, Prasanna, Mravic, Marco, Stawiski, Eric W, Vargas, Derek, Durinck, Steffen, Gupta, Ravi, Khanna-Gupta, Arati, Trabucco, Sally E, Sokol, Ethan S, Hartmaier, Ryan J, Singh, Ashish, Chougule, Anuradha, Trivedi, Vaishakhi, Dutt, Amit, Patil, Vijay, Joshi, Amit, Noronha, Vanita, Ziai, James, Banavali, Sripad D, Ramprasad, Vedam, DeGrado, William F, Bueno, Raphael, Jura, Natalia, and Seshagiri, Somasekar

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Genetics, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Adult, Animals, Antineoplastic Agents, Cell Line, Tumor, Female, Humans, Lung Neoplasms, Male, Mice, Mice, Inbred BALB C, Middle Aged, Molecular Dynamics Simulation, Mutation, Protein Conformation, Protein Domains, Protein Kinase Inhibitors, Receptor, ErbB-2, Signal Transduction, Receptor, erbB-2, ERBB2 activation, ERBB2 structure, ERBB2/HER2, HER2 germline mutation, HER2 kinase inhibitors, HER2 somatic mutation, anti-HER2 antibodies, juxtamembrane (JMD) domain mutation, transmembrane domain (TMD) mutation, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) that include G660D, R678Q, E693K, and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the TMD/JMD mutations function by improving the active dimer interface or stabilizing an activating conformation. Further, we found that HER2 G660D employed asymmetric kinase dimerization for activation and signaling. Importantly, anti-HER2 antibodies and small-molecule kinase inhibitors blocked the activity of TMD/JMD mutants. Consistent with this, a G660D germline mutant lung cancer patient showed remarkable clinical response to HER2 blockade.

Published
2018

11. Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23

Author

Liu, Lijun, Thaker, Tarjani M, Freed, Daniel M, Frazier, Nicole, Malhotra, Ketan, Lemmon, Mark A, and Jura, Natalia

Subjects
Biochemistry and Cell Biology, Biological Sciences, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dimerization, ErbB Receptors, Phosphorylation, Phosphotransferases, Signal Transduction, EGFR, ERBB receptors, HER receptors, LET-23, allosteric kinase activation, asymmetric dimerization, kinase activation, kinase structure, receptor tyrosine kinase signaling, Chemical Sciences, Information and Computing Sciences, Biophysics, Biological sciences, Chemical sciences
Abstract

In the active HER receptor dimers, kinases play distinct roles; one is the catalytically active kinase and the other is its allosteric activator. This specialization enables signaling by the catalytically inactive HER3, which functions exclusively as an allosteric activator upon heterodimerization with other HER receptors. It is unclear whether the allosteric activation mechanism evolved before HER receptors functionally specialized. We determined the crystal structure of the kinase domain of the only EGF receptor in Caenorhabditis elegans, LET-23. Our structure of a non-human EGFR kinase reveals autoinhibitory features conserved in the human counterpart. Strikingly, mutations within the putative allosteric dimer interface abrogate activity of the isolated LET-23 kinase and of the full-length receptor despite these regions being only partially conserved with human EGFR. Our results indicate that ancestral EGFRs have built-in features that poise them for allosteric activation that could facilitate emergence of the catalytically dead, yet functional, orthologs.

Published
2018

14. Single-use duodenoscope for ERCP performed by endoscopists with a range of experience in procedures of variable complexity

Author

Slivka, Adam, Chennat, Jennifer S., Khalid, Asif, Das, Rohit, Singh, Harkirat, Vipperla, Kishore, Sejpal, Divyesh V., Lee, Calvin, Antony, Andrew, Kozarek, Richard A., Ross, Andrew S., Choi, Jun-Ho, Larsen, Michael, Law, Joanna, Krishnamoorthi, Rajesh, Klair, Jagpal, Muthusamy, V. Raman, Thaker, Adarsh, Petersen, Bret T., Martin, John A., Abu Dayyeh, Barham, Chandrasekhara, Vinay, Levy, Michael, Law, Ryan, Pleskow, Douglas K., Cohen, Jonah M., Bruno, Marco J., Poley, Jan-Werner, Peetermans, Joyce A., Rousseau, Matthew J., Tirrell, Gregory P., Insull, Jeff, and Thaker, Adarsh M.

Published
2021
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23. Anatomic location of Barrett’s esophagus recurrence after endoscopic eradication therapy: development of a simplified surveillance biopsy strategy

Author

Omar, Mahmoud, Thaker, Adarsh M., Wani, Sachin, Simon, Violette, Ezekwe, Eze, Boniface, Megan, Edmundowicz, Steven, Obuch, Joshua, Cinnor, Birtukan, Brauer, Brian C., Wood, Mariah, Early, Dayna S., Lang, Gabriel D., Mullady, Daniel, Hollander, Thomas, Kushnir, Vladimir, Komanduri, Srinadh, and Muthusamy, V. Raman

Published
2019
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29. Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass

Author

Ponsky, Jeffrey, Greenwald, Bruce D., Uradomo, Lance T., McGhan, Alyson A., Hakimian, Shahrad, Ross, Andrew, Sherman, Stuart, Bick, Benjamin L., Forsmark, Christopher E., Yang, Dennis, Gupte, Anand, Chauhan, Shailendra, Hughes, Steven J., Saks, Karen, Bakis, Gennadiy, Templeton, Adam W., Saunders, Michael, Sedarat, Alireza, Evans, John A., Muniraj, Thiruvengadam, Gardner, Timothy B., Ramos, Almino C., Santo, Marco Aurelio, Nett, Andrew, Coté, Gregory A., Elmunzer, B. Joseph, Dua, Kulwinder S., Nosler, Michael J., Strand, Daniel S., Yeaton, Paul, Kothari, Shivangi, Ullah, Asad, Taunk, Pushpak, Brady, Patrick, Pinkas, Haim, Faulx, Ashley L., Shahid, Haroon, Holmes, Jordan, Pannu, Davinderbir, Komanduri, Srinadh, Bucobo, Juan Carlos, Dhaliwal, Harry, Rostom, Alaa, Acker, Brent W., Abbas, Ali M., Strong, Andrew T., Diehl, David L., Brauer, Brian C., Lee, Iris H., Burbridge, Rebecca, Zivny, Jaroslav, Higa, Jennifer T., Falcão, Marcelo, El Hajj, Ihab I., Tarnasky, Paul, Enestvedt, Brintha K., Ende, Alexander R., Thaker, Adarsh M., Pawa, Rishi, Jamidar, Priya, Sampath, Kartik, de Moura, Eduardo Guimarães Hourneaux, Kwon, Richard S., Suarez, Alejandro L., Aburajab, Murad, Wang, Andrew Y., Shakhatreh, Mohammad H., Kaul, Vivek, Kang, Lorna, Kowalski, Thomas E., Pannala, Rahul, Tokar, Jeffrey, Aadam, A. Aziz, Tzimas, Demetrios, Wagh, Mihir S., and Draganov, Peter V.

Published
2018
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32. Structural and Magnetic Studies on La2-xDyxCa2xBa2Cu4+2xOz Type Superconducting Oxides

Author

Rayaprol, S., Kundaliya, Darshan C., Thaker, C. M., Kuberkar, D. G., Chakraborty, Keka R., Krishna, P. S. R., and Ramanadham, M.

Subjects
Condensed Matter - Superconductivity
Abstract

The La-2125 type La2-xDyxCa2xBa2Cu4+2xOz (0.1 < x < 0.5; LDBO) compounds have been synthesized and studied for their structural and superconducting properties by room temperature neutron diffraction, high field dc magnetization, four-probe resistivity and iodometric double titration. The Rietveld analysis of the neutron diffraction data reveals tetragonal structure for all the samples, which crystallizes into La-123 type tetragonal structure in P4/mmm space group. Iodometric double titrations were performed to determine the oxygen content values and calculate mobile charge carrier (holes) density. The superconducting transition temperatures (Tc) increases from ~ 20 K for x = 0.1 to a maximum of 75 K for x = 0.5. Flux pinning force (Fp) and critical current density (Jc), calculated from the low temperature hysteresis loops, also increases with increasing dopant concentration. The paper presents the studies on structure and superconducting properties of all LDBO compounds in light of the role of calcium in inducing superconductivity in the tetragonal non-superconducting oxide., Comment: To appear in J. Phys. Condens. Matter

Published
2004
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33. Critical current density and flux pinning in La2-xPrxCa2xBa2Cu4+2xOz (x = 0.1 - 0.5) superconductors

Author

Rayaprol, S., Thaker, C. M., Shah, N. A., and Kuberkar, D. G.

Subjects
Condensed Matter - Superconductivity
Abstract

Polycrystalline La2-xPrxCa2xBa2Cu4+2xOz (LPCaBCO) compounds with x = 0.1 - 0.5 were synthesized by solid-state reaction method and studied by room temperature X-ray diffraction, dc resistivity, dc magnetization and iodometry. The superconducting transition temperatures in these tetragonal triple perovskite compounds increases from 32 to 62 K (Tconset values) with increasing dopant concentration. The mixing of rare earth La3+ and Pr3+/4+ ions at rare earth site (La3+) along with substitution of divalent Ca2+ results in the shrinkage of unit cell volume. The contraction of unit cell volume due to larger ion being substituted by smaller ions, gives rise to creation of pinning centers in the unit cell leading to increase in critical current density and flux pinning, Comment: To be published in Solid State Communications (2004)

Published
2004
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34. Studies on La2-xPrxCayBa2Cu4+yOz (0.1 < x < 0.5) type mixed oxide superconductors

Author

Rayaprol, S, Mavani, K R, Rana, D S, Thaker, C M, Dixit, Manglesh, Bhattacharya, Shovit, and Kuberkar, D G

Subjects
Condensed Matter - Superconductivity
Abstract

The La2-xPrxCayBa2Cu4+yOz (LaPrCaBCO) mixed oxides have been studied for their structural and superconducting properties using X-ray diffraction (XRD), d. c. resistivity, d. c. susceptibility and iodometric double titration. All the LaPrCaBCO samples for x = 0.1 - 0.5, exhibit tetragonal crystalline structure with P 4/mmm space group as determined by Rietveld analysis of the X-ray diffraction data. With increasing x, enhancement in Tc is observed, which is quite interesting for Pr substituted high Tc oxides. Maximum Tc ~ 58 K has been observed for x = 0.5(La-2125 stoichiometry). The results of structural studies and superconducting property measurements are presented in light of increase in Tc in LaPrCaBCO system with increasing Pr concentration., Comment: 6 pages including 5 figures and 1 table

Published
2003
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35. Effect of Mo-Substitution on Superconductivity, Flux Pinning and Critical Currents of la(1.5)Nd(0.5)Ca(1)Ba(2)Cu(5)O(z0

Author

Rayaprol, S., Mavani, Krushna, Thaker, C. M., Rana, D. S., Kulkarni, R. G., Kuberkar, D. G., Kundaliya, Darshan, and Malik, S. K.

Subjects
Condensed Matter - Materials Science, Condensed Matter - Superconductivity
Abstract

Mo-substituted triple perovskite superconducting samples with the stoichiometric composition La(1.5)Nd(0.5)Ca(1)Ba(2)[Cu(1-x)Mo(x)](5)O(z), [LNCBCuMO] with x = 0.00, 0.01, 0.03, 0.05 and 0.10, have been investigated using X-ray diffraction, electrical resistivity, magnetic susceptibility, magnetization and oxygen content measurements. The observed reduction in Tc with increasing Mo content (x) in LNCBCuMO, can be attributed to the decrease in hole concentration. Magnetization measurements as a function of temperature and field (H), exhibit an M-H hysteresis loop, which indicates moderate flux pinning, which can be attributed to the pinning centers created by Mo substitution at Cu sites. The critical current density, Jc, deduced from the M-H data satisfies the flux creep model., Comment: 30 Pages, 9 Figures, In Press Physica C

Published
2003
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50. Shilajit

Author

Bhavsar, Shailesh K., primary, Thaker, Aswin M., additional, and Malik, Jitendra K., additional

Published
2016
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