- PhD, Life Sciences, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India, 1994 – 2000
- MSc, Biotechnology, School of Biotechnology, Madurai Kamaraj University, Tamil Nadu, India, 1992-1994
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.