Assoc Prof Catherine Day

Biochemistry Department University of Otago P.O. Box 56 710 Cumberland St Dunedin 9054 , New Zealand Tel.: +64 3 479-7871 FAX: +64 3 479-7866 e-mail: catherine.day@stonebow.otago.ac.nz

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. Recently this knowledge has underpinned the development of several new anti-cancer compounds.

Research in my laboratory is primarily focused on understanding how a number of proteins involved in apoptosis interact and then how this knowledge can be exploited for the development of improved therapeutics. To achieve these goals we collaborate with a number of groups.

Our recent research has focused on characterisation of the Bcl-2 family of proteins and the complexes these proteins form, these studies have given a detailed picture of the interaction interface and suggested ways to develop selective molecules.

More recently, modification of proteins by ubiquitylation has also been shown to have an important role in regulating apoptosis. RING domain E3-ligases mediate transfer of ubiquitin from the E2, which is bound to the RING domain, to the substrate protein that is also recruited by the RING-bearing protein. Although substrate ubiquitylation is routinely observed, a detailed understanding of ubiquitin transfer remains elusive. Recent work in my laboratory has focused on characterizing the ubiquitin E3-ligase activity of several proteins that have a C-terminal RING domain. New anti-cancer agents trigger E3-ligase activity but the details of this remain elusive. Our goal is to develop a molecular understanding that will aid development of better therapeutic compounds.

Funding

Marsden Fund
Lottery Health
University of Otago Research Grant

Selected Recent Publications

Mace, P.D., Shirley, S. & Day, C.L. (2009) Assembling the Building Blocks: Structure and Function of Inhibitor of Apoptosis Proteins. Cell Death Differ. (in press)

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

Mace, P.D., Linke, K., Feltham, R., Schumacher, F-R, Smith, C.A., Vaux, D.L., Silke, J. & Day, C.L. (2008) Structures of the cIAP2 RING Domain Reveal Conformational Changes Associated with Ubiquitin-conjugating Enzyme (E2) Recruitment. J. Biol Chem. 283, 31633-40.

Day, C. L., Smits, C., Fan, F. C., Lee, E. F., Fairlie, W. D. and Hinds, M. G. (2008) Structure of the BH3-domains from the p53 inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. J. Mol. Biol. 380, 958-971.

Smits, C., Czabotar, P. E., Hinds, M.G. and Day, C. L. (2008) Structural plasticity underpins promiscuous binding of the pro-survival protein A1. Structure 16, 818-829.

Linke, K., Mace, P., Smith, C. A., Vaux, D. L., Silke, J. and Day, C. L. (2008) Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ. 15, 841-848.

Czabotar, P.E., Lee, E.F., van Delft, M. F., Day, C. L., Smith, B.J., Huang, D.C., Fairlie, W.D., Hinds, M.G. & Colman, P. M. (2007) Structural insights into the degradation of Mcl-1 induced by BH3 domains. PNAS 104, 6217-22 (link)                       

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

Hinds, M. G. & Day, C. L. (2005) Regulation of apoptosis: uncovering the binding determinants. Current Opinions of Structural Biology 16, 690-699.

Silke, J., Kratina, J., Chu, D., Ekert, P.G., Pakusch, M., Day, C.L., Huang, D.C.S & Vaux, D.L. (2005) Determination of Cell Survival by RING-mediated Regulation of IAP Abundance. PNAS 102, 16182-16187.

Day, C. L., Chen, L., Richardson, S., Harrison, P. J., Huang, D. C. S. & Hinds, M. G. (2005) Understanding the structural basis for specific binding of BH3-only ligands by Mcl-1. J. Biol. Chem. 280, 4738-4745.

Chen, L., Willis, S., Wei, A., Smith, B. J., Fletcher, J. I., Hinds, M. G., Colman, P. M., Day, C. L., Adams, J. M. & Huang, D. C. S (2005) Differential targeting of pro-survival Bcl-2 proteins by their pro-apoptotic BH3-only ligands. Molecular Cell 17, 393-404.

Hinds, M. G., Lackmann, M., Skea, G. L., Harrison, P. J., Huang, D. C. S. & Day, C. L. (2003) The Structure of Bcl w Reveals a Role for the C-terminal Residues in Modulating Biological Activity. EMBO J. 22, 1497-1507.

Silke, J., Ekert, P. G., Day, C. L., Hawkins, C. J., Baca, M., Chew, J., Pakusch, M., Verhagen, A. M. & Vaux, D. L. (2001) Genetic and biochemical evidence that direct inhibition of caspase 3 is dispensible for the anti-apoptotic activity of XIAP. EMBO J. 20, 3114-3123.

Day, C. L. & Alber, T. A. (2000) Crystal structure of the amino terminal domain from the tumor suppressor protein APC. J. Molecular Biology 301, 149-158

Hinds, M. G., Norton, R. S., Vaux, D. L. & Day, C. L. (1999) Solution structure of the baculoviral IAP repeat (BIR) domain. Nature Structural Biology, 6, 648-651.