Indian Institute of Science, Bangalore, India. 1991

Postdoctoral Research
Cell Biology, Yale University School of Medicine, U.S.A. 1991-1997

Research Interests
Biology of molecular chaperones, Infectious Diseases of Animal and Human, Genomics, Proteomics and Metabolomics


Email : tatu@biochem.iisc.ernet.in
Research Interests

My research aims to decipher the functions of molecular chaperones in cellular context. Chaperones are well known for their ability to assist protein folding, facilitate protein assembly, prevent protein denaturation and renature misfolded proteins. Biochemical activities and molecular mechanisms of chaperone function have been elegantly studied by reconstituting purified components outside the cell. However the broader impact of chaperone function in cell growth and development is only beginning to be appreciated.

A. Development HSP90 Directed Anti-Cancer Drugs:

Molecular chaperone, HSP90, evolutionarily conserved regulates more than 200 proteins with respect to constitutive cell signaling and responses to stress. This chaperon has been used by cancer cells to regulate numerous oncoproteins and hence HSP90 inhibition seems to offer a unique anticancer strategy. In my lab, we carry out exploration of novel HSP90 inhibitors to combat cancer. The approach involves in vitro drug binding assay and animal experiments.

B. Veterinary healthcare:

Agrarian economies like India heavily depend on animals for their agricultural practices. Animal health care has been of major concern in most developed countries. With increase in the incidence of zoonotic diseases there is a growing demand to address animal infections in terms of their prevention and treatment. Further more there is a big gap between veterinary health care and technology applications in developing countries. My group is trying to bridge this gap by studying neglected animal infections such as animal trypanosomiasis using modern tools of biology. Our long term goal is to find better control measures as well as therapeutic strategies. Efforts are being made to develop better diagnostic tools as well as new drug development.

C. Neglected infectious diseases:

1. Malaria

It is well known that the parasite experiences a temperature shock of over 10°C during its entry in the vertebrate host. Furthermore, during febrile episodes in the patient the parasite is exposed to a heat shock (up to 41°C) due to rise in the body temperature of the host. How does the parasite react to these rapid temperature fluctuations? What are the protective mechanisms employed by the parasite to counter cellular damage? Experiments performed in my group in the last 10 year have shed some light on these mechanisms.

Using biochemical, cellular as well as proteomic approaches we have characterized the expression, localization and complexes of abundant chaperones of the class Hsp40, Hsp60, Hsp70, Hsp90 and Hsp100 expressed by the parasite in human red blood cells. Our studies show an essential role for Hsp90 of the parasite and implicate it as a potential drug target against malaria. Pharmacological inhibitors specific to Hsp90 are currently being examined as candidate drugs against malaria.(Pallavi R et al., JBC 2010, Pallavi R et al., Plos One 2011, Acharya P et al., Proteomics CA 2009)

The red blood cells undergo extensive remodelling during the course of infection. The cytosol of RBC acquires number of membranous compartments such as Maurers clefts and the cell membrane undergoes modifications to form protrusions know as knobs on its surface. Knobs make erythrocytes rigid and cytoadherent and are largely responsible for the severity of the disease. To bring about these changes parasite exports multiple proteins into the host cell. It is a challenging task for the parasite as it resides in a vacuole inside the RBC and the proteins need to transverse multiple membranes in order to reach their final destinations. It is being speculated that this process of protein trafficking requires an intricate involvement of chaperones owing to their ability to fold, unfold and stabilize proteins. Also, the exported proteins (especially the components of knobs) have a tendency to remain in a disordered conformation due to the presence of homorepeats and prion-like domains in their primary structure. A major group among the class of exported proteins is constituted by chaperones and surprisingly all of them belong to the Hsp40 family. We are interested in understanding the specific roles played by these Hsp40s in the process of host cell remodelling. Towards this, we have generated antisera against some exported Hsp40s and carry out in vivo experiments involving immunofluorescence and immunoprecipitation analysis to determine the localization and interacting partners of the protein respectively.

2. Surra

            Trypanosoma evansi

Surra is caused by Trypanosoma evansi infection. It is a veterinary protozoan disease most common in the cows, buffaloes, horses and other cattle. The disease has been listed as one of the major concern by World Organisation for Animal Health (OIE) in 2011 and is common in tropical countries. My laboratory works on understanding the role of chaperones in the progress of disease in host. We have shown important role of Heat Shock Protein 90 from T. evansi (TeHsp90) by using Hsp90 directed inhibitor called 17-AAG (17-allyl amino 17-demethoxy geldanamycin). We are now progressing towards starting animal trials against the disease using the above mentioned inhibitors.(Pallavi R et al., JBC 2010, Roy N et al., Plos One 2010)

3. Giardiasis

Heat shock protein 90 plays diversified roles in different microbes. Like any other pathogen Giardia lamblia also uses heat shock protein machinery to survive under stress full conditions put forth by host. Mass spectrometric analysis of Hsp90 from G.lamblia, revealed a novel trans-splicing based expression of GlHsp90 in this minimalist protozoan parasite. We have recently shown that Hsp90 in Giardia is arranged as a split gene, HspN and HspC separated by 777 kb intergenic sequence. The full length Hsp90 transcript is a resultant of a novel trans-splicing phenomenon which is mediated by spliceosomal complex. The mature full length transcript has all the hallmarks of the canonical Hsp90. The protein band that corresponded to a region of around 80 kDa was identified to be GlHsp90. Hence we provide evidence for such a reconstruction mechanism at proteomic level. Sequencing of the junctional peptide by MS/MS provides evidence of functional full length Hsp90 in Giardia, a novel approach to identify trans-splicing event using mass spectrometry. (Nageshan RK et al., JBC 2011, Roy N et al., Biochim Biophys Acta 2011)

4. Amoebiasis

            Entamoeba histolytica

We are also examining the importance of Hsp90 in Entamoeba histolytica. The microbe is responsible for a most common clinical problem called as amoebiasis.

D. Targeted Drug Discovery:

While deciphering the novel molecular targets and pathways my group also uses anasamycin antibiotics as model organic molecules to understand the role of heat shock proteins in stress during the infection.(Pallavi R et al., JBC 2010)

              Control                            Treated

E. Model Systems:

In addition to examining infectious protozoa, my laboratory also uses Dictyostelium discoideum and Saccharomyces cerevisiae to understand functions of Heat shock protein 90 and its co-chaperones in Biology.(Sawarkar R, Roy N et al., J Mol. Biol. 2008, Wider D et al.,Mol Biochem Parasitol. 2009)

1. Dictyostelium discoideum

2. Saccharomyces cerevisiae

F. Role of ER chaperones in protein folding:

My group is also examining folding of secretory proteins in the ER of animal cells. By reconstituting the oxidative folding of retinol binding protein (RBP) in isolated ER we are examining the mechanisms underlying selective retention of apo forms of RBP in the ER.(Sundar Rajan Selvaraj et al., Mol Biol Cell. 2008)

G. Proteomic and Bioinformatic activities:

My group plays a leading role in mining the proteome data from the variety of biological exudates, coming directly from infected human/animal subjects by using state of the art proteomics and bioinformatics tools . We have successfully worked on the clinical proteomes of Plasmodium falciparum, Plasmodium vivax, Giardia lamblia and Trypanosoma evansi infections.(Kumar Y et al., Proteomics 2004, Khachane A et al., J Proteome Res. 2005, Pallavi R et al., Plos One 2011, Acharya P et al., Proteomics CA 2009)