Madhusudan Dey
Assistant Professor
Molecular Biology

Office: Lapham 464
Phone: 414-229-4309
FAX: 414-229-3926

Research Interests

My lab uses Saccharomyces cerevisiae (yeast) to explore the structure-function and activation of protein kinases involved in cellular stress and the mechanism of translational repression and translocation of mRNA. Though my research interests are broad, my lab is focused on three specific research projects:

Molecular mechanism of protein kinase domain activation of Protein Kinase R and Inositol-requiring kinase 1: Protein kinase PKR provides the first line of defense against viral infections whereas IRE1 initiates a signal transduction pathway to overcome the endoplasmic reticulum (ER) stress caused by pathogen infection and/or metabolic stress. In collaborative projects, we resolved the structures of the kinase domains of both PKR and IRE1. The crystal structures revealed that both kinase domains dimerize, and we observed that the dimeric architecture of the two kinases is strikingly similar despite their unique functions in distinct cellular pathways. Given their shared architecture and their common requirement for autophosphorylation during activation, we are studying the mechanism of activation of the dimeric kinases PKR and IRE1.

Coupled translational repression and translocation of the HAC1 mRNA: During the ER stress, the active IRE1 specifically cleaves two RNA hairpins in the yeast HAC1 mRNA to remove an intron, and subsequently the two exons are re-ligated. This cleavage and ligation (splicing) of HAC1 mRNA requires relocation of the mRNA to the site of IRE1 on the ER. Interestingly, translation of the HAC1 mRNA is repressed during this relocation, which is mediated by an element in the 3-UTR (3’-untranslated region) of the HAC1 mRNA. We are studying the coupling between translational repression and translocation of the HAC1 mRNA.

Inhibition of translation factor eIF2B by phospho-eIF2α: We revealed the mechanism of dimerization, activation, and substrate recognition by the family of stress responsive kinases PKR, GCN2, PERK and HRI that phosphorylate the translation factor eIF2α. Phosphorylation of eIF2α results in tight binding of eIF2 to its GDP/GTP exchange factor eIF2B. This tight binding of eIF2 inactivates eIF2B and thereby inhibits protein synthesis. We continue our studies to reveal the molecular mechanism(s) underlying how phosphorylated eIF2α inhibits the function of eIF2B.

Teaching Interests

My teaching interests are in an introductory molecular biology course, an upper level course (see below) and a seminar based discussion course: 

Bio 587: Molecular Signal Transduction – U/G level course
This course will cover the basics of signal transduction, the mechanistic details of the signal transduction network, and approaches to signaling pathway-based drug design. Also, this course is designed to provide a modern concept on how a cell perceives external stimuli (e.g. information on environmental changes) and how the detected signals are used to coordinate the function of various organelles so as to integrate the perceived information into an all-or-none decision (see attached syllabus).

Bio 597: RNA Structure, Function and Metabolism – U/G level course
Molecular biology is a vast subject, and over the past three decades, major advances have been made in ribonucleic acid (RNA) research. As a result, the ‘RNA world’ hypothesis has been formulated that places RNA at the origin of life. The functional repertoire of RNA is incredibly vast. RNA can carry genetic information (e.g. RNA genomes of viruses), serve as the chemical blueprint for protein synthesis (messenger RNA), and regulate gene expression (e.g. micro RNA). Remarkably, RNA molecules can also act as enzymes (ribozymes) that catalyze various biological reactions. This course is designed to provide comprehensive coverage of RNA biology as a key to our understanding of life (see attached syllabus).

Bio 671: Undergrad Seminar-Microbiology
This course is for senior undergrad students who are interested in molecular biology and microbiology research. The course will provide a brief history of molecular biology and an overview how research is done and published. The course will be in the form of seminars where students will present a research topic and participate in classroom discussions.

Selected Publications

  1. Dey, M., Chiu, E., Velyvis, A., Kay, L. E., Sicheri, F., Deter T. E., (2011) Requirement for kinase-induced conformational change in eIF2α restricts phosphorylation of Ser-51 Proceedings of the National Academy of Sciences, USA (in press).
  2. Dev, K., Santangelo T. J., Rothenburg, S., Neculai, D., Dey, M., Sicheri, F., Dever, T. E., Reeve, J. N., Hinnebusch, A. G. Archaeal aIF2B interacts with eukaryotic translation initiation factors eIF2alpha and eIF2Balpha: Implications for aIF2B function and aIF2B regulation. (2009) Journal of Molecular Biology, 392, 701-22.
  3. Garriz, A., Qiu, H., Dey, M., Seo, E. J., Dever, T. E., Hinnebusch, A. G. A network of hydrophobic residues impeding helix alphaC rotation maintains latency of kinase Gcn2, which phosphorylates the alpha subunit of translation initiation factor 2. (2009) Molecular and Cellular Biology, 29, 1592-607.
  4. Rothenburg, S., Deigendesch, N., Dey, M., Dever, T. E., Tazi, L. Double-stranded RNA-activated protein kinase PKR of fishes and amphibians: varying number of double-stranded RNA binding domains and lineage specific duplications. (2008) BMC Biology, 6, 12.
  5. Lee, K. P. K., Dey, M, Dante, N., Cao, C., Dever, T. E., Sicheri, F. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. (2008) Cell, 132, 89-100.
    i.   Preview: Ron, D. and Hubbard, S. R. How IRE1 Reacts to ER Stress. (2008) Cell, 132, 24-26.
  6. Moraes, M. C. S., Jesus, T. C. L., Hashimoto, N. N., Alves, A. S., Avila, C. C., Dey, M., Dever, T. E., Schenkman, S., Castilho, B. A. A novel transmembrane kinase phosphorylates the unusual form of the translation initiation factor 2α of Trypanosoma brucei. (2007) Eukaryotic Cell, 6, 1979-91.
  7. Dey, M., Cao, C., Sicheri, F., and Dever, T. E. Conserved salt-bridge interactions required for activation of protein kinases PKR, GCN2 and PERK. (2007) Journal Biological Chemistry, 282, 6653-6660.
  8. Dey, M., Cao, C., Dar, A., Tamura, T., Ozato, K., Sicheri, F., and Dever, T. E. Mechanistic link between protein kinase PKR catalytic domain dimerization, autophosphorylation and eIF2α phosphorylation. (2005) Cell, 122, 901-913.
    i.   Preview I: Taylor, S. S., Haste, N. M., Ghosh, G. PKR and eIF2alpha: integration of kinase dimerization, activation, and substrate docking. (2005) Cell, 122, 823-825.
    ii. Preview II: Hinnebusch A. G. eIF2alpha kinases provide a new solution to the puzzle of substrate specificity. (2005) Nature Structure and Molecular Biology, 12, 835-838.
  9. Dey, M., Trieselmann, B., Locke, E. G., Lu, J., Cao, C., Dar, A., Krishnamurthy, T., Dong, J., Sicheri, F., and Dever, T. E. PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor eIF2B recognize overlapping surfaces on translation factor eIF2. (2005) Molecular and Cellular Biology, 25, 3063-75.
  10. Sharma N, Dey, M., and Schaar, S. C. Evidence of two forms of poly (A) polymerase in germinated wheat embryos and their regulation by a novel protein kinase. (2002) Biochemical and Biophysical Research Communications, 293, 403-411.
  11. Dey, M., and Choudhury, S. Genetically modified organism – A Brave New World! (2001) Current Science, 80, 722-723.
  12. Dey, M., and Guha-Mukherjee, S. Aspartate metabolism in Cicer immature seeds requires Ca2+, protein phosphorylation and dephosphorylation. (2000) Plant Science, 150, 85-91.
  13. Dey, M., and Guha-Mukherjee, S. Phytochrome activation of aspartate kinase in etiolated chickpea (Cicer arietinum) seedling. (1999) Journal of Plant Physiology, 154, 454-458.
  14. Dey, M., Kalia, S., Ghosh, S., and Guha-Mukherjee, S. Biochemical and molecular basis of differentiation in plant tissue culture. (1998) Current Science, 74, 591-596.