Danny Hatters
For more information on Danny and his research, visit his 'Find an Expert' page
Detecting and mapping different protein conformations in live cells
Many cellular functions are driven by changes in the conformation of proteins; some conformational changes act as molecular switches for regulating normal cellular activities, while others are non-normal and result in detrimental outcomes to the cell. Our laboratory studies how proteins change conformation in live cells and how different conformations engage with the surrounding cellular machinery.
A key platform is the development of new fluorescence-based approaches for visualization of distinct conformations of specific disease associated proteins, such as those involved in cancer and neurodegenerative disease.
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Fig 1. Huntingtin aggregation in the cellular environment. Are monomers, oligomers or aggregates toxic? How do they influence the cellular machinery? What is their temporal and spatial localization? |
Tracking the aggregation kinetics of mutant proteins in cells
A major area of research is defining how abnormal conformations of mutant proteins aggregate and interfere with the cellular machinery. One such protein we study is huntingtin, which when mutated causes Huntington’s disease. Huntington’s disease is a devastating neurodegenerative disease often striking individuals mid life. The disease is caused by an abnormally long polyglutamine repeat length near the amino-terminus of huntingtin. The extra glutamines cause the protein to change conformation, aggregate and form large aggregates known as inclusions.
In vivo Drosophila models of Huntington’s disease
For a more comprehensive view on how protein structure, conformation and aggregation play roles in intact living systems we are developing novel Drosophila models of Huntington’s disease in collaboration with Dr Leonie Quinn, in the department of Cell Biology and Anatomy. We are devising novel imaging approaches, which includes live-cell imaging, to specifically examine protein dynamics in vivo.
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Fig 2. We are developing new tools to track huntingtin aggregation and conformational change directly in vivo in Drosophila, such as in these salivary gland cells |
Visualizing “on” and “off” kinase conformations in cells
In collaboration with Dr Terry Mulhern, we are using novel structure-guided approaches to develop sensors that can map where different kinase conformations accumulate in live cells. We anticipate this will enable a better understanding of how “on” and “off” forms of kinases specifically interact with different cellular proteins and ligands, and how the different forms are trafficked around the cell.
Current questions and projects
- Why are altered conformations of huntingtin toxic?
- How do misfolded huntingtin conformations interfere with the cellular machinery?
- How does the length of polyglutamine affect the conformation of huntingtin?
- How does the cell engage with misfolded and aggregating proteins?
- Where do different kinase conformations accumulate in the cell?
Approaches
In addition to the methods described above, our more general philosophy is to apply multidisciplinary approaches to solve our problems. Typically these include classic biophysics and structural biology approaches for examining protein structure and function, and genetics and classic cell biology approaches for examining how proteins work in their natural environment.
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Fig 3. Mutant huntingtin protein assembles into long tangled fibrils in vitro |
Recent publications:
- Olshina MA, Angley LM, Ramdzan YM, Tang J, Bailey MF, Hill AF and Hatters DM (2010). Tracking mutant huntingtin aggregation kinetics in cells reveals three major populations including an invariant oligomer pool. J Biol Chem 285, 21807-21816.
- Ramdzan YM, Nisbet RM, Miller J, Finkbeiner S, Hill AF and Hatters DM (2010). Conformation sensors that distinguish monomeric proteins from oligomers in live cells. Chem Biol 17, 371-379.
- Tetali SD, Budamagunta MS, Simion C, den Hartigh LJ, Kalai T, Hideg K, Hatters DM, Weisgraber KH, Voss JC, and Rutledge JC. (2010). VLDL lipolysis products increase VLDL fluidity and convert apolipoprotein E4 into a more expanded conformation. J Lipid Res 51, 1273-1283.
- Coleman BM, Nisbet RM, Han S, Cappai R, Hatters D and Hill AF (2009). Conformational detection of prion protein with biarsenical labeling and FlAsH fluorescence. Biochem Biophys Res Commun 380, 564-568.
- Hatters DM, Voss JC, Budamagunta MS, Newhouse YN and Weisgraber KH. (2009). Insight on the molecular envelope of lipid-bound apolipoprotein E from electron paramagnetic resonance spectroscopy. J Mol Biol 386, 261-271.
- Hatters DM. (2008). Protein misfolding inside cells: The case of huntingtin and Huntington's Disease. IUBMB Life 60, 724-728.
Lab members, June 2010
In photo (left to right):Yasmin Ramdzan, Yuan Qi Wong, Danny Hatters,Saskia Polling, Kevin Lim, Sevgi Irtegun, Ben Scicluna
Members not in photo:Yee-Foong Mok, Julia McCoey, Jinwei Tang
Lab personnel
Head
Dr Danny Hatters
Research staff
Yee-Foong Mok (Research associate)
Yasmin Mohamed Ramdzan (Research assistant)
Graduate students
Sevgi Irtegun
Saskia Polling
Jinwei Tang
Yuan Qi Wong
Honours students
Kevin Lim
Julia McCoey
Benjamin Scicluna