All India Institute of Medical Sciences, New Delhi
National Centre for Cell Science, Pune
Biological macromolecules specifically, proteins are the workhorses performing critical functions essential for diverse cellular and biological processes. Structure-function aspects of how these molecular machines work with exemplary accuracy, specificity and speed has always fascinated me and has been a key driving force to pursue my research interests in this area.
The opportunity to get a first hand experience and training, working with proteins and understanding their structure-function came when I joined laboratory of Prof. Tej P. Singh at All India Institute of Medical Sciences (AIIMS), New Delhi to pursue my PhD research. I worked on a class of glycoproteins expressed in mammary glands during involution which were implicated as protective-signaling factors that determine which cells are to survive the drastic tissue remodeling that occurs during this period. My thesis work gave insights into possible mechanism of action of these proteins. During my PhD, in 2003, Roderick MacKinnon was awarded Noble prize in chemistry for his work on potassium ion channels. I was mesmerized by his noble lecture explaining the molecular mechanisms of ion selectivity in these receptors. This filled me with a strong desire and motivation to pursue my future research in the field of ion channels; and led me to join laboratory of Dr. Mark Mayer at National Institutes of Health (NIH), Bethesda, USA for my postdoctoral research. At NIH I, focused on understanding how ionotropic glutamate receptors (iGluRs) function at the molecular level. iGluRs are responsible for the major excitatory neurotransmission in mammalian central nervous system and play key roles in neural development, synaptic plasticity, motor function, learning and memory formation. For the first part of my postdoctoral work, I focused on answering a very fundamental problem in the field: What are the molecular mechanism and principles that regulate the assembly of iGluRs? We showed that the extracellular Amino Terminal Domain (ATD) of the iGluRs plays key roles in the assembly process. Our work gave insights into the assembly of iGluR tetramers of defined subunit composition. We also showed for the first time that the ATD domains facilitate the efficient assembly of heteromeric iGluRs. The results were published as a series of research papers in top ranked journals and an invited review in the Annual Review of Physiology. In recognition of the excellence of this work, I also won two Fellows Award for Research Excellence (FARE) at NIH, and presented my results at three Gordon Research conferences as well as at poster and platform presentations at international meetings of the Biophysical Society. During the later part of my stint at NIH, I worked on determining the full-length receptor structure of an AMPAR and Kainate-type iGluRs trapped in various states of their activity. These membrane receptors with their large extracellular domains pose an even greater challenge to already tough field of membrane protein crystallography. However, we made significant progress and have been able to optimize expression and purification of these receptors for crystallographic purposes and cryo-EM imaging studies. The training received during my doctoral and postdoctoral research has geared me to undertake structure - function studies on ion channels as an independent researcher. Further, financial support received from Wellcome Trust/DBT India Alliance as an intermediate fellow will surely provide much needed boost during these early days as an independent investigator.