Young, Jason C. - McGill University - Department of Biochemistry

研究领域

A fundamental biological process is the conversion of genetic information into functional proteins. Linear protein molecules must fold into sophisticated three-dimensional structures, and interact with the appropriate cellular targets. In cells, the folding and maturation of proteins depend on a specialized class of proteins termed 'molecular chaperones'. The chaperones are critical for the prevention of protein misfolding and aggregation, which are thought to underlie several neurodegenerative disorders such as Parkinson's disease. Two of the most important chaperones in the eukaryotic cytosol are Hsp70 and Hsp90, the 70 kDa and 90 kDa heat shock proteins. The function of both chaperones involves interactions with a variety of regulatory co-chaperone proteins whose activities are still poorly understood. My research investigates the biochemical mechanisms of chaperone and co-chaperone activity, and the consequences of this essential activity at a cellular level. Interestingly, Hsp70 and Hsp90 work not only in the folding of soluble proteins, but also help in other cellular processes. These include the targeting of certain precursor proteins to the mitochondria for import into that organelle. Chaperones also work in the regulated assembly or disassembly of protein complexes on other intracellular membranes. It seems that specific co-chaperones are used for the different functions of Hsp70 and Hsp90. Key questions are how the various co-chaperones direct the activities of the chaperones, for folding and for other purposes, and how chaperone function is integrated into the biogenesis of cellular structures. A combination of biochemistry, molecular and cell biology techniques are being applied to these exciting questions.

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Rodina, A., Patel, P.D., Kang, Y., Patel, Y., Baaklini, I., Wong, M.J., Taldone, T., Yan, P., Yang, C., Maharaj, R., Gozman, A., Patel, MR., Patel, H.J., Chirico, W., Erdjument-Bromage, H., Talele, T.T., Young, J.C. & Chiosis, G. (2013) Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein. Chem. Biol. 20, 1469-1480. Baaklini, I., Wong, M. J., Hantouche, C., Patel, Y., Shrier, A. & Young, J. C. (2012) The DNAJA2 substrate release mechanism is essential for chaperone-mediated folding. J. Biol. Chem. 287, 41939-41954. Fan, A.C.Y., Kozlov, G., Hoegl, A., Marcellus, R.C., Wong, M.J.H., Gehring, K. & Young, J.C. (2011) Interaction between the human mitochondrial import receptors Tom20 and Tom70 in vitro suggests a chaperone displacement mechanism. J. Biol. Chem. 286, 32208-32219. Okiyoneda, T., Barrière, H., Bagdány, M., Rabeh, W.M., Du, K., Höhfeld, J., Young, J.C. & Lukacs, G.L. (2010) Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329, 805-810. Tzankov, S., Wong, M.J.H., Shi, K., Nassif, C. & Young, J.C. (2008) Functional divergence between co-chaperones of Hsc70. J. Biol. Chem. 283, 27100-27109. Bhangoo, M.K., Tzankov, S., Fan, A.C.Y., Dejgaard, K., Thomas, D.Y. & Young, J.C. (2007) Multiple 40-kDa Heat Shock Protein chaperones function in Tom70-dependent mitochondrial import. Mol. Biol. Cell 18, 3414-3428. Fan, A.C.Y., Bhangoo, M.K. & Young, J.C. (2006) Hsp90 functions in the targeting and outer membrane translocation steps of Tom70-mediated mitochondrial import. J. Biol. Chem. 281, 33313-33324. Young, J.C., Agashe, V.R., Siegers, K. & Hartl, F.U. (2004) Pathways of chaperone mediated protein folding in the cytosol. Nature Reviews Mol. Cell. Biol. 5, 781-791. Young JC, Barral JM, and Hartl FU. (2003) More than folding: Localized functions of cytosolic chaperones. Trends Biochem. Sci. 28, 541-547. Brychzy A, Rein T, Winklhofer KF, Hartl FU, Young JC, and Obermann WMJ. (2003) Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system. EMBO J. 22, 3613-3623. Young JC, Hoogenraad NJ, and Hartl FU. (2003) Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112, 41-50. Sondermann H, Ho AK, Listenberger LL, Siegers K, Moarefi I, Wente SR, Hartl FU, and Young JC. (2002) Prediction of novel Bag-1 homologs based on structure/function analysis identifies Snl1p as an Hsp70 co-chaperone in Saccharomyces cerevisiae. J. Biol. Chem. 277, 33220-33227. Young JC, Moarefi I, and Hartl FU. (2001) Hsp90: a specialized but essential protein folding tool. J. Cell Biol. 154, 267-273. Young JC, and Hartl FU. (2000) Polypeptide release by Hsp90 involves ATP hydrolysis and is enhanced by the co-chaperone p23. EMBO J. 19, 5930-5940.