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Dr. Prem S. Kaushal

Assistant Professor
E-mail: prem dot kaushal at rcb dot res dot in

  • PhD 2010, Indian Institute of Science, Bangalore, INDIA
  • Postdoc, Case Western Reserve University, Cleveland, OH, USA
  • Research Affiliate, Wadsworth Center, Albany, NY, USA
  • Staff Scientist, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, INDIA

Structural aspects of translation regulation & ribosome biogenesis

Translation, one of the key step in central dogma of the molecular biology, is the process in which genetic information present in mRNA is decoded into a polypeptide. Nearly 40% of the known antibiotics target different stages of translation in bacteria. Our laboratory’s research goal is to unravel the functioning of macromolecular complexes involved in translation regulation and ribosome biogenesis by applying an integrated approach involving cryo- electron microscopy (cryo-EM), X-ray crystallography, molecular biology and biochemistry techniques. The structural insights would be useful to find new drug targets and improve the efficacy of existing antibiotics. Currently, lab is focusing on to understand the translation strategies that Mycobacterium tuberculosis (Mtb) adopts in dormancy and how mega Dalton protein synthesis machinery, the ribosome, assembles inside the cell.

Translation in dormancy

MTb, causative agent of the tuberculosis (Tb), becomes dormant, non-replicating and phenotypically drug resistant when it encounters multiple stresses inside the host macrophages, a condition known as latent tuberculosis infection (LTBI) or dormancy. Nearly, one third of world’s population possesses LTBI from which ~10% of LTBI infected individuals develop acute Tb infection. Current drugs have proved to be inefficient in eradicating tubercle bacilli in latent lesion therefore LTBI serve as an enormous reservoir of tuberculosis. Further, during dormancy mycobacterium slows down cellular processes including translation. The dormancy survival regulon (DosR regulon) up regulate 48 genes that appear to play crucial roles in dormancy. By mimicking the stress environment of host macrophages in laboratory conditions, our lab is trying to elucidate the unique features of protein synthesis during dormancy that leads to the better understanding of the life cycle of Mtb pathogen.

Ribosome biogenesis

Ribosomes are the ribonucleoprotein (RNP) complexes of mega Dalton (MDa) size, consist of two subunits, a large subunit (LSU) having peptidyl transferase activity and a small subunit (SSU) which is responsible for decoding mRNA. In prokaryotes, the cytoplasmic ribosomes are 2.7 MDa RNP complexes. The LSU, contains 34 ribosomal proteins (RPs) and 23S, and 5S rRNAs, whereas SSU, contains 21 RPs and 16S rRNA. Ribosome assembly occurs in stages which involves the synthesis, processing, and modification of individual components (rRNAs and RPs), and their assembly. Defects in ribosome assembly are known as ribosomopathy and are associated with various diseases such as Diamond-Blackfan anemia, Cartilage hair hypoplasia, cancer etc. Our goal is to trap ribosomes in intermediate stage of assembly by depleting ribosome biogenesis factors and determine cryo-EM structure of assembly intermediate.

Cryo-EM

Cryo-EM is a fast emerging powerful technique in modern biology, which uses very cold temperature (liquid nitrogen) to visualize the macromolecular complex in its native state without distorting the structure of the molecule. Recent advancement in the electron detector technology, allows direct recording of electrons without converting them to photons and image-processing techniques, now makes it is possible to achieve atomic resolution. The recent cryo-EM structures of complex with drug molecules have further proven the power of the cryo-EM technique to visualize the binding sites of drug molecules and its application in inhibitor design.

X-ray crystallography

X-ray crystallography remains the most powerful technique over a century for the structure determination of proteins and biological macromolecules. The atomic co-ordinate obtained from X-ray crystal structure provides platform for structure based drug design, site directed mutagenesis, elucidation of enzyme mechanisms, specificity of protein–ligand interactions etc.

  • DST-SERB Early Career Research Award (2019)
  • CSIR Senior Research Fellowship (2005-2008)
  • CSIR Junior Research Fellowship (2003-2005)
  • Republic day (1996) Prashasti Patr (Citation) recipient form district administration for achievements in the field of Science.
  • Outstanding team effort prize winner in reflective type telescope making workshop at CSIO, Chandigarh, 1995.
  • Our model on “water purification by solar energy” was displayed in National Science Exhibition 1995 at Pragati Maidan, New Delhi and published by NCERT in 1995.
  • Two time first prize winner at state level Science Fair in Origami (Chamba 1993 & Shimla 1994).

Highly motivated researchers interested in structural biology, particularly, in Cryo- electron microscopy (Cryo- EM) and X-ray crystallography are requested to contact directly to the PI.

  • Niraj Kumar
    Junior Research Fellow

  • Sheenam
    Junior Research Fellow

  • Shivani Sharma
    Junior Research Fellow (Project)

Alumni

  • Sukriti Chowdary (Summer-Internship 2019)
  • Anjali Sharma (Six months dissertation 2020)
  • Dr. Wahab Khan (NPDF 2019-20)
  1. Koripella RK, Sharma MR, Bhargava K, Datta PP, Kaushal PS, Keshavan P, Spremulli LL, Banavali NK & Agrawal RK. (2020) Structures of the human mitochondrial ribosome bound to EF-G1 reveal distinct features of mitochondrial translation elongation. Nat Commun 11, 3830 https://doi.org/10.1038/s41467-020-17715-2

  2. Li Y, Sharma MR, Koripella RK, Yong Y, Kaushal PS, Lin Q, Wade JT, Gray TA, Derbyshire KM, Agrawal RK, & Ojha AK. (2018) Zinc depletion induces ribosome hibernation in mycobacteria. Proceedings of the National Academy of Sciences USA (PNAS) 115:8191-6.

  3. Qu G *, Kaushal PS*, Wang J*, Shigematsu H, Piazza CL, Agrawal RK, Belfort M & Wang HW. Structure of group II intron complexed with its transcriptase. (2016) Nature Structure and Molecular Biology (NSMB) 23, 549-57. (*equal contributions). Highlighted as the News and Views in NSMB 23, 507-9 and a follow up review in RNA BIOLOGY 13, 1218-22.

  4. Kaushal PS*, Sharma MR*, Booth TM, Haque E, Tung C, Sanbonmatsu KY, Spremulli LL and Agrawal R K. (2014) Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome. Proceedings of the National Academy of Sciences USA (PNAS) 111(20), 7284-9 (*equal contributions).

  5. Ahmad MF, Kaushal PS, Wan, Q, Wijeratna SR, An X, Huang M & Dealwis CD. (2012) Role of arginine-293 and glutamine-288 in communication between catalytic and allosteric sites in yeast ribonucleotide reductase. Journal of Molecular Biology 419, 315-29.

  6. Kaushal PS, Singh P, Sharma A, Muniyappa K & Vijayan M. (2010) X-ray and molecular dynamics studies on Mycobacterium leprae single-stranded DNA binding protein and comparison with other eubacterial SSB structures. Acta Crystallographica D66, 1048-58

  7. Kaushal PS, Talawar RK, Varshney U & Vijayan M. (2010) Structure of uracil-DNA glycosylase from Mycobacterium tuberculosis. Insights into interactions with ligands. Acta Crystallographica F66, 887-92 (cover illustration).

  8. Kaushal PS, Talawar RK, Krishna PD, Varshney U & Vijayan M. (2008). Unique features of the structure and interactions of mycobacterial uracil-DNA glycosylase: structure of a complex of the Mycobacterium tuberculosis enzyme in comparison with those from other sources. Acta Crystallographica D64, 551-560.

  9. Kaushal PS, Sankaranarayanan R & Vijayan M. (2008) Water-mediated variability in the structure of relaxed-state haemoglobin. Acta Crystallographica F64, 463-9.

  10. Singh P, Talawar RK, Krishna PD, Varshney U & Vijayan M. (2006) Overexpression, purification, crystallization and preliminary X-ray analysis of uracil N-glycosylase from Mycobacterium tuberculosis in complex with a proteinaceous inhibitor. Acta Crystallographica F62, 1231-4

  11. Reviews

    • Kaushal PS, Sharma MR and Agrawal RK. (2015) The 55S mammalian mitochondrial ribosome and its tRNA-exit region. Biochimie. 114, 119-26.

    • Wijerathna SR, Ahmad MF, Xu H, Fairman JW, Zhang A, Kaushal PS, Wan Q, Kiser J & Dealwis CG. (2011) Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy. Pharmaceuticals, 4(10),1328-54

    Book chapters

    • Sharma MR, Kaushal PS, Gupta M, Banavali N K, & Agrawal RK. (2013) Insights into structural basis of mammalian mitochondrial translation. In Translation in Mitochondria and Other Organelles, Duchene, A.M. ed. (Springer-Verlag, Berlin/ Heidelberg), pp. 1-28.

    • Kaushal PS, Wan Q, Faber C, & Dealwis C. (2012) Crystal dehydration Technique. In Crystallography: Research, Technology and Applications, Hokkaido, M. and Nagano, E. ed. (Nova Science Publishers, Inc.), pp. 91-104

Dr. Prem Singh Kaushal
Regional Centre for Biotechnology
NCR Biotech Science Cluster
3rd Milestone, Faridabad-Gurgaon Expressway
P.O. Box No. 3, Faridabad - 121 001
Haryana (NCR Delhi), India
E-mail: prem dot kaushal at rcb dot res dot in
Phone: 91 129-2848980 

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