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SPOTLIGHT ON: Andrey Shubin Background After completing both a Bachelors and Masters Degree in Chemical Technology and Biotechnology at Moscow State University of Fine Chemical Technology, I was enrolled in a PhD course in Biotechnology at the Institute of Molecular Genetics of Russian Academy of Sciences (IMG RAS). From the beginning of my research activity I have been working at the Laboratory of Protein Engineering (IMG RAS) under the supervision of Dr. Ilya Demidyuk. The main objectives of investigation in our laboratory are proteolytic enzymes; with a core focus on their maturation and activation pathways, mechanisms of substrate recognition and functioning, as well as possible applications of proteases in medicine and industry. My current PhD project considers proteases as potential therapeutic agents with the capability to induce death of cancer cells. In the course of the project we have found that one of the tested enzymes - 3C protease of human hepatitis A virus - has a prominent cytotoxic effect, accompanied by massive cytoplasmic vacuolation. Since the vacuolation might result from the impairment of autophagy pathway and could reflect a natural role of the protease during infection, I was interested in uncovering a deeper characterisation of this effect. Luckily, due to the Australia Awards Fellowship Program, I have an excellent opportunity to carry this out at the Yeast Laboratory here at Monash University under the supervision of Professor Rod Devenish. Projects All the research projects I participate in are related to different aspects of proteolytic enzyme functioning. One of the investigations considers the information value of expression profiling of proprotein convertases (PC) and matrix metalloprotease (MMP) genes in malignant tissues of human lungs. The key function of PC is processing and/ Newsletter: April 2011, Issue 22 or activation of numerous proteins and peptides, many of which are associated with malignant diseases. MMPs are substrates of PCs and key factors in tumor invasion and metastasis. Systems of PCs and MMPs respond to malignant transformation, which suggests their expression status can be utilised as a possible marker for cancer typing and prognosis. The most interesting result of the project obtained so far is evidence that expression of PCs and MMPs genes in human lung tumors changes in a limited number of scenarios. These scenarios are characterised by a sharp increase in the expression level of a single PC without significant changes in expression of other proteases. We believe this result reflects the different pathways of tumor development and hope to confirm this finding in other types of cancer. Our laboratory is also focused on the investigation of the roles of propeptides in protease functioning. Most proteases are synthesised as propeptide-containing Department of Biochemistry and Molecular Biology precursors. These structural elements can determine folding of the cognate protein, function as an inhibitor/activator peptides, mediate enzyme sorting, and the interaction of a protease with other molecules and supramolecular structures. Even minor changes in propeptide structure can crucially alter protein function in the living organism. Modulatory activity coupled with high variation allows one to consider propeptides as specific evolutionary modules that can transform biological properties of proteases without significant changes in the highly conserved catalytic domains. As the considered properties of propeptides are not unique to proteases, propeptide-mediated evolution seems to be a universal biological mechanism. For our investigations, we use the thermolysin-like M4 protease family as an experimental model. We have revealed that according to structure of their propeptides, M4 proteases are divided into two distinct groups, even though the mature enzymes have largely similar sequences. Proteases of the first group have relatively long propeptides, are known to act as intramolecular chaperones and inhibitors of cognate mature proteins. Proteins of the second group have short propeptides and resemble protealysin from Serratia proteamaculans. We have obtained a crystal structure of protealysin (which was the first example of thermolysin-like peptidase precursor crystal structure) and revealed an inhibitor function of its short propeptide. However, the existence of two different groups of propeptides makes one think that short propeptides have other specific functions which are still to be clarified. In spite of our focus in the fields mentioned above, we are always interested in collaborations and new projects related to different aspects of protease functioning and keen to broaden our research horizons. Page 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Newsletter: April 2011, Issue 22 RECENT PUBLICATIONS Buckle, A.M., M.A. Bate, S. Androulakis, M. Cinquanta, J. Basquin, F. Bonneau, D.K. Chatterjee, D. Cittaro, S. Graslund, A. Gruszka, R. Page, S. Suppmann, J.X. Wheeler, D. Agostini, M. Taussig, C.F. Taylor, S.P. Bottomley, A. Villaverde, and A. de Marco, Recombinant protein quality evaluation: proposal for a minimal information standard. Stand Genomic Sci, 2011. 5(2): p. 195-197 Denton, A.E., R. Wesselingh, S. Gras, C. Guillonneau, M.R. Olson, J.D. Mintern, W. Zeng, D.C. Jackson, J. Rossjohn, 3P.D. Hodgkin, P.C. Doherty, and S.J. Turner, Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses. J Immunol, 2011. 187(11): p. 5733-5744 Heinz, E. and T. Lithgow, Back to basics: A revealing secondary reduction of the mitochondrial protein import pathway in diverse intracellular parasites. Biochim Biophys Acta, 2012 E-pub. Knaupp, A.S. and S.P. Bottomley, Structural change in beta-sheet A of Z alpha(1)-antitrypsin is responsible for accelerated polymerization and disease. J Mol Biol, 2011. 413(4): p. 888-98 Ou, L., D. Duan, J. Wu, E.C. Nice, and C. Huang, The Application of High-throughput siRNA Screening Technology to Study Host- Pathogen Interactions. Comb Chem High Throughput Screen, 2012. 15(4): p. 299-205 Kinross, K.M., K.G. Montgomery, M. Kleinschmidt, P. Waring, I. Ivetac, A. Tikoo, M. Saad, L. Hare, V. Roh, T. Mantamadiotis, K.E. Sheppard, G.L. Ryland, I.G. Campbell, K.L. Gorringe, J.G. Christensen, C. Cullinane, R.J. Hicks, R.B. Pearson, R.W. Johnstone, G.A. McArthur, and W.A. Phillips, An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest, 2012. 122(2): p. 553-7 Pelosi, A., D. Smith, R. Brammananth, A. Topolska, H. Billman-Jacobe, P. Nagley, P.K. Crellin, and R.L. Coppel, Identification of a Novel Gene Product That Promotes Survival of Mycobacterium smegmatis in Macrophages. PLoS One, 2012. 7(2): p. e31788 [MICRO,BCH] Poreba, M., S. McGowan, T.S. Skinner-Adams, K.R. Trenholme, D.L. Gardiner, J.C. Whisstock, J. To, G.S. Salvesen, J.P. Dalton, and M. Drag, Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum. PLoS One, 2012. 7(2): p. e31938 Rada, P., P. Dolezal, P.L. Jedelsky, D. Bursac, A.J. Perry, M. Sedinova, K. Smiskova, M. Novotny, N.C. Beltran, I. Hrdy, T. Lithgow, and J. Tachezy, The core components of organelle biogenesis and membrane transport in the hydrogenosomes of Trichomonas vaginalis. PLoS One, 2011. 6(9): p. e24428 Reantragoon, R., L. Kjer-Nielsen, O. Patel, Z. Chen, P.T. Illing, M. Bhati, L. Kostenko, M. Bharadwaj, B. Meehan, T.H. Hansen, D.I. Godfrey, J. Rossjohn, and J. McCluskey, Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor. J Exp Med, 2012. 209(4): p. 761-74 Tilkorn, D.J., E.M. Davies, E. Keramidaris, A.M. Dingle, Y.W. Gerrand, C.J. Taylor, X.L. Han, J.A. Palmer, A.J. Penington, C.A. Mitchell, W.A. Morrison, G.J. Dusting, and G.M. Mitchell, The in vitro preconditioning of myoblasts to enhance subsequent survival in an in vivo tissue engineering chamber model. Biomaterials, 2012. E-pub: p. 1-12 Wagstaff, K.M., H. Sivakumaran, S.M. Heaton, D. Harrich, and D.A. Jans, Ivermectin is a specific inhibitor of importin alpha/betamediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J, 2012. 443(3): p. 851-856 Wu, J., N. Xie, X. Zhao, E.C. Nice, and C. Huang, Dissection of aberrant GPCR signaling in tumorigenesis--a systems biology approach. Cancer Genomics Proteomics, 2012. 9(1): p. 37-50 Yoga, Y.M., D.A. Traore, M. Sidiqi, C. Szeto, N.R. Pendini, A. Barker, P.J. Leedman, J.A. Wilce, and M.C. Wilce, Contribution of the first K-homology domain of poly(C)-binding protein 1 to its affinity and specificity for C-rich oligonucleotides. Nucleic Acids Res, 2012. E-pub: p. 1-14 Zhou, Y., Y.S. Zhou, F. He, J. Song, and Z. Zhang, Can simple codon pair usage predict protein-protein interaction? Mol Biosyst, 2012. E-pub Department of Biochemistry and Molecular Biology Page 9
Page 1 and 2: Newsletter Department of Biochemist
Page 3 and 4: Prof Trevor Lithgow continued TJL l
Page 5 and 6: INTRODUCING: Dr Ruby Law Newsletter
Page 7: FIRST AIDERS & BREATHING APPARATUS

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