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Department of Biochemistry profile

Professor Catherine Day

PositionHead of Department
DepartmentDepartment of Biochemistry
QualificationsBSc(Hons) PhD(Massey)
Research summaryProtein to protein interactions; structural biology

Research

Many key events within cells are regulated by the appropriate interaction of two proteins. Understanding the molecular basis of protein-protein interactions is central to elucidation of these cellular processes and can lead to the development of new or improved therapeutic compounds.

Scientific image.I am interested in understanding how a number of proteins involved in apoptosis interact, and how this knowledge can be exploited for the development of improved anti-cancer compounds. Most recently, we have focused on characterisation of processes that result in attachment of ubiquitin to proteins because our analysis of the Inhibitor of Apoptosis (IAP) proteins showed that ubiquitin is important for their regulation.

Scientific image.Modification of proteins by ubiquitin relies on an enzyme cascade (see figure above) that culminates in an E3 protein. E3-ligases that possess a RING domain mediate transfer of ubiquitin from the E2 to the substrate protein that is recruited by the E3. Although substrate ubiquitylation is routinely observed, a detailed understanding of ubiquitin transfer remains elusive. Research in my laboratory has focused on characterisation of the ubiquitin E3-ligase activity of proteins that have a C-terminal RING domain. Our goal is to understand how interaction of the RING domain with the E2 (see figure below) promotes transfer of ubiquitin from the E2 to the substrate. It is hoped that a molecular understanding will allow manipulation of this process by therapeutic compounds.

Current projects in my laboratory are focused on understanding the mechanisms that control ubiquitin transfer, including the role of RING dimerisation, the mechanisms by which the E2 influences the ubiquitin modification and the role of ubiquitin binding domains. Collaboration with other research groups is an important component of these projects.

Positions available

Enquires about projects from prospective graduate students and postdoctoral fellows are welcome and should be sent to catherine.day@otago.ac.nz.

For information about scholarships for postgraduate students go to the University of Otago website otago.ac.nz/postgraduate

Funding

Research in my laboratory is funded by the Health Research Council of New Zealand, the Marsden Fund, Lottery Health NZ and University of Otago Research Grants.

Awards

  • 2014, Elected as Fellow of the Royal Society of New Zealand
  • 2010, Otago School of Medical Sciences Distinguished Researcher of the Year
  • 2010, New Zealand Society for Biochemistry and Molecular Biology Life Technologies Award
    This is the premier award of the Society and is awarded annually for outstanding scientific research.

Publications

Wright, J. D., Mace, P. D., & Day, C. L. (2016). Noncovalent ubiquitin interactions regulate the catalytic activity of ubiquitin writers. Trends in Biochemical Sciences, 41(11), 924-937. doi: 10.1016/j.tibs.2016.08.003

Foglizzo, M., Middleton, A. J., & Day, C. L. (2016). Structure and function of the RING domains of RNF20 and RNF40, dimeric E3 ligases that monoubiquitylate histone H2B. Journal of Molecular Biology, 428(9), 4073-4086. doi: 10.1016/j.jmb.2016.07.025

Wright, J. D., Mace, P. D., & Day, C. L. (2016). Secondary ubiquitin-RING docking enhances Arkadia and Ark2C E3 ligase activity. Nature Structural & Molecular Biology, 23(1), 45-52. doi: 10.1038/nsmb.3142

Middleton, A. J., & Day, C. L. (2015). The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. Scientific Reports, 5, 16793. doi: 10.1038/srep16793

Budhidarmo, R., & Day, C. L. (2014). The ubiquitin-associated domain of cellular inhibitor of apoptosis proteins facilitates ubiquitylation. Journal of Biological Chemistry, 289(37), 25721-25736. doi: 10.1074/jbc.M113.545475

Journal - Research Article

Wright, J. D., Mace, P. D., & Day, C. L. (2016). Secondary ubiquitin-RING docking enhances Arkadia and Ark2C E3 ligase activity. Nature Structural & Molecular Biology, 23(1), 45-52. doi: 10.1038/nsmb.3142

Foglizzo, M., Middleton, A. J., & Day, C. L. (2016). Structure and function of the RING domains of RNF20 and RNF40, dimeric E3 ligases that monoubiquitylate histone H2B. Journal of Molecular Biology, 428(9), 4073-4086. doi: 10.1016/j.jmb.2016.07.025

Wright, J. D., Mace, P. D., & Day, C. L. (2016). Noncovalent ubiquitin interactions regulate the catalytic activity of ubiquitin writers. Trends in Biochemical Sciences, 41(11), 924-937. doi: 10.1016/j.tibs.2016.08.003

Middleton, A. J., & Day, C. L. (2015). The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. Scientific Reports, 5, 16793. doi: 10.1038/srep16793

Condon, S. M., Mitsuuchi, Y., Deng, Y., LaPorte, M. G., Rippin, S. R., Haimowitz, T., … Bettjeman, B., Cumming, M. H., … Day, C. L., & Chunduru, S. K. (2014). Birinapant, a Smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies. Journal of Medicinal Chemistry, 57(9), 3666-3677. doi: 10.1021/jm500176w

Budhidarmo, R., & Day, C. L. (2014). The ubiquitin-associated domain of cellular inhibitor of apoptosis proteins facilitates ubiquitylation. Journal of Biological Chemistry, 289(37), 25721-25736. doi: 10.1074/jbc.M113.545475

Nakatani, Y., Kleffmann, T., Linke, K., Condon, S. M., Hinds, M. G., & Day, C. L. (2013). Regulation of ubiquitin transfer by XIAP, a dimeric RING E3 ligase. Biochemical Journal, 450(3), 629-638. doi: 10.1042/BJ20121702

Schumacher, F.-R., Wilson, G., & Day, C. L. (2013). The N-terminal extension of UBE2E ubiquitin–conjugating enzymes limits chain assembly. Journal of Molecular Biology, 425, 4099-4111. doi: 10.1016/j.jmb.2013.06.039

Budhidarmo, R., Nakatani, Y., & Day, C. L. (2012). RINGs hold the key to ubiquitin transfer. Trends in Biochemical Sciences, 37(2), 58-65. doi: 10.1016/j.tibs.2011.11.001

Feltham, R., Bettjeman, B., Budhidarmo, R., Mace, P. D., Shirley, S., Condon, S. M., … Day, C. L. (2011). Smac mimetics activate the E3 ligase activity of cIAP1 protein by promoting RING domain dimerization. Journal of Biological Chemistry, 286(19), 17015-17028. doi: 10.1074/jbc.M111.222919

Lopez, J., John, S. W., Tenev, T., Rautureau, G. J. P., Hinds, M. G., Francalanci, F., … Day, C. L., & Meier, P. (2011). CARD-mediated autoinhibition of cIAP1's E3 ligase activity suppresses cell proliferation and migration. Molecular Cell, 42(5), 569-583. doi: 10.1016/j.molcel.2011.04.008

Mace, P. D., Shirley, S., & Day, C. L. (2010). Assembling the building blocks: Structure and function of inhibitor of apoptosis proteins. Cell Death & Differentiation, 17, 46-53. doi: 10.1038/cdd.2009.45

Feltham, R., Moulin, M., Vince, J. E., Mace, P. D., Wong, W. W.-L., Anderton, H., Day, C. L., … Silke, J. (2010). Tumor necrosis factor (TNF) signaling, but not TWEAK (TNF-like weak inducer of apoptosis)-triggered cIAP1 (cellular inhibitor of apoptosis protein 1) degradation, requires cIAP1 RING dimerization and E2 binding. Journal of Biological Chemistry, 285(23), 17525-17536. doi: 10.1074/jbc.M109.087635

Liew, C. W., Sun, H., Hunter, T., & Day, C. L. (2010). RING domain dimerization is essential for RNF4 function. Biochemical Journal, 431(1), 23-29. doi: 10.1042/BJ20100957

Risk, J. M., Laurie, R. E., Macknight, R. C., & Day, C. L. (2010). FRIGIDA and related proteins have a conserved central domain and family specific N- and C- terminal regions that are functionally important. Plant Molecular Biology, 73, 493-505. doi: 10.1007/s11103-010-9635-2

Mace, P. D., Smits, C., Vaux, D. L., Silke, J., & Day, C. L. (2010). Asymmetric recruitment of cIAPs by TRAF2. Journal of Molecular Biology, 400, 8-15. doi: 10.1016/j.jmb.2010.04.055

Risk, J. M., Day, C. L., & Macknight, R. C. (2009). Reevaluation of abscisic acid-binding assays shows that G-Protein-Coupled Receptor2 does not bind abscisic acid. Plant Physiology, 150(1), 6-11.

Dewson, G., Kratina, T., Czabotar, P., Day, C. L., Adams, J. M., & Kluck, R. M. (2009). Bak activation for apoptosis involves oligomerization of dimers via their α6 helices. Molecular Cell, 36(4), 696-703. doi: 10.1016/j.molcel.2009.11.008

Mabbitt, P. D., Rautureau, G. J. P., Day, C. L., Wilbanks, S. M., Eaton-Rye, J. J., & Hinds, M. G. (2009). Solution structure of Psb27 from cyanobacterial photosystem II. Biochemistry, 48(37), 8771-8773. doi: 10.1021/bi901309c

Vince, J. E., Pantaki, D., Feltham, R., Mace, P. D., Cordier, S. M., Schmukle, A. C., … Day, C. L., … Silke, J. (2009). TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (TNF) to efficiently activate NF-κB and to prevent TNF-induced apoptosis. Journal of Biological Chemistry, 284(51), 35906-35915. doi: 10.1074/jbc.M109.072256

Risk, J. M., Macknight, R. C., & Day, C. L. (2008). FCA does not bind abscisic acid. Nature, 456(7223), E5-E6.

Smits, C., Czabotar, P. E., Hinds, M. G., & Day, C. L. (2008). Structural plasticity underpins promiscuous binding of the prosurvival protein A1. Structure, 16(5), 818-829. doi: 10.1016/j.str.2008.02.009

Day, C. L., Smits, C., Fan, F. C., Lee, E. F., Fairlie, W. D., & Hinds, M. G. (2008). Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. Journal of Molecular Biology, 380(5), 958-971. doi: 10.1016/j.jmb.2008.05.071

Linke, K., Mace, P. D., Smith, C. A., Vaux, D. L., Silke, J., & Day, C. L. (2008). Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death & Differentiation, 15(5), 841-848. doi: 10.1038/sj.cdd.4402309

Mace, P. D., Linke, K., Feltham, R., Schumacher, F.-R., Smith, C. A., Vaux, D. L., … Day, C. L. (2008). Structures of the cIAP2 RING domain reveal conformational changes associated with ubiquitin-conjugating enzyme (E2) recruitment. Journal of Biological Chemistry, 283(46), 31633-31640.

Hinds, M. G., Smits, C., Fredericks-Short, R., Risk, J. M., Bailey, M., Huang, D. C. S., & Day, C. L. (2007). Bim, Bad and Bmf: Intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death & Differentiation, 14, 128-136.

Czabotar, P. E., Lee, E. F., van Delft, M. F., Day, C. L., Smith, B. J., Huang, D. C. S., … Colman, P. M. (2007). Structural insights into the degradation of Mcl-1 induced by BH3 domains. PNAS, 104(15), 6217-6222.

van Delft, M. F., Wei, A. H., Mason, K. D., Vandenberg, C. J., Chen, L., Czabotar, P. E., … Day, C. L., … Huang, D. C. S. (2006). The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell, 10(5), 389-399.

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