SAHA INSTITUTE OF NUCLEAR PHYSICS
Department of Atomic Energy, Govt. of India
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In Crystallography and Molecular Biology Division multifaceted approaches are used to study the structure and conformation of proteins which are involved in various regulatory processes in biology under normal and diseased conditions. Therefore, one of the major focuses of the Division is to study the structure and dynamics of proteins and determination of the 3D structures to gain functional insights. Post-translational modification of proteins is an important mechanism to regulate their structures and functions. In this context, the mechanism of phosphorylation and the structural elements that direct the phosphorylation to occur with high fidelity in case of fructokinase and ribokinase have been figured out with high resolution structures. The structures of Psu and the cage structure of an Acylphosphatase drew much attenction in recent past. Structure of Psu, solved by Hg-SAD method, revealed a novel fold with a unique knotted dimerisation. The 12-meric nano-cage (~8 nm) structure of acylphosphatase from Vibrio choleraeO395 (Vc-AcP), coupled with studies in solutions illuminates the basis for the formation of the cage, while a single (Cys20→Arg) mutation (Vc-AcP-C20R) transforms Vc-AcP to a potent enzyme, but disrupts the assembly into a trimer. Since it is interesting and also useful to engineer protein to obtain useful mechanistic information and modify functional specificity, one of the major focuses of divisional research is ‘Structure-based protein engineering’ to alter activity, stability and specificity of proteolytic enzymes. The spacio-temporal regulation of proteolytic activity of cysteine proteases by their cognate pro-domain and through specific inhibitors of serpin family are being studied at structural and molecular level. Moreover, the important questions regarding protein folding are also addressed through theoretical and experimental approaches with cyclophilin as a model system. Differential gene expression is regulated at transcriptional level as well as through various posttranscriptional mechanisms regulating RNA turnover and translation. It has been shown that in case of disease causing Leishmania parasites an octamer motif in the untranslated regions (UTRs) of mRNAs is responsible S-phase specific periodic stability of the messages and a large multidomain riboendonuclease cleaves the mRNAs differentially in a monoubiquitination dependent manner. Interestingly, octamer motifs have been found in 5’UTRs of several cell cycle regulated genes also in human and their importance in differential stability of the messages and regulation of translation is being investigated. Effect of posttranslational modifications like phosphorylation of some replication factor on initiation step of DNA replication is also being investigated. Cell cycle dependent genome-wide interaction of some initiation proteins with replication origins in human cells will be studied using high throughput ChIP-Seq approach in our newly installed Next Generation Sequencing platform. The parasitic diseases leishmaniases and growing resistance of the causative parasites to the existing regime of drugs are serious health concern in several countries including India. Works are also focused on bioinformatics related to the leishmanial genome and crystallography of the proteins from the same group of parasites that could be potential drug targets. The basis of development of drug resistance in some of the strains of Leishmania parasites are also being studied using high throughput sequencing approach. One of the key components of cell is the plasma membrane which along with many embedded and associated proteins and its dynamic interaction with cytoskeleton such as spectrin is responsible for maintaining the shape of cell, selective transfer of materials and communication with outside. Recombinant fragments of different structural domains of erythroid and non-erythroid spectrin are being designed, cloned and expressed for further studies using spectroscopic, biochemical and biophysical approaches in the context of lipid-protein interactions and chaperone activities. A laboratory for the study of structure and dynamics of membrane proteins equipped with single-channel electrophysiology and electron magnetic resonance (EPR) spectroscopy together with fluorescence techniques are being established to generate functionally compatible models of novel membrane proteins under physiological conditions that are not amenable to crystallographic approaches. It has been found that chaperone-like protein HYPK interacts with the first 17 amino acid region of the protein Huntingtin (HTT) and modulates mutant HTT-mediated toxicity. Altered microRNA expression has already been implicated in HD pathogenesis. We have demonstrated the transcriptional regulation of multiple miRNAs (miR-100, miR-146a, miR-150) in human and mouse cells and also identified miR-432 as the first miRNA known to be regulated by Heat Shock Factor 1. Investigation is underway on the post-transcriptional regulation of Mitofusin 2 (MFN2) via miR-214 and transcriptional regulation by a transcription factor E2F1.

 

Last Updated on Thursday, 11 August 2016 13:47
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