Geoff Howlett
Research interests: Amyloid fibril formation and protein misfolding diseases
Proteins self-assemble into toxic amyloid fibrils in a number of age-related diseases including dementia, diabetes and heart disease. Our research group aims to discover the mechanism that drives normal proteins to form amyloid fibrils and to develop inhibitors that block and reverse fibril growth.
Amyloid fibril formation by human apolipoprotein C-II provides a convenient experimental system for our studies. Our research uses several technologies including analytical ultracentrifugation, fluorescence, NMR and mass spectroscopy to explore the formation and breakdown of amyloid fibrils and the interactions of fibrils with other amyloid components. Our strategy to develop inhibitors is potentially applicable to a range of amyloid fibrils of clinical importance.
Projects
Honours and PhD projects are offered in the following areas:
- The design and characterization of small molecular weight inhibitors of amyloid fibril formation
- The effect of fibril morphology on the function of apolipoprotein fibrils
- NMR structural analysis of amyloid core peptides
- In vitro mutagenesis of human apolipoproteins and analysis of the effects of mutations on the assembly and function of amyloid fibrils
Lab personnel
HeadAssociate Professor Geoff HowlettResearch staffDr Michael Griffin (Research fellow)Graduate studentsTim Ryan Honours studentsSimon Maaser |
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| Geoff Howlett | Mike Griffin | Katrina Binger | Tim Ryan | Chai Lean Teoh |
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| Yang Shuo | Simon Maaser | Zach Rosenes | Vino Nair |
Selected recent publications
2008
- Hung A, Griffin MD, Howlett GJ, Yarovsky I. (2008) 'Effects of oxidation, pH and lipids on amyloidogenic peptide structure: implications for fibril formation?', Eur Biophys J.
- Binger KJ, Griffin MD, Howlett GJ. (2008) 'Methionine oxidation inhibits assembly and promotes disassembly of apolipoprotein C-II amyloid fibrils', Biochemistry, 47, 10208-10217.
- Lees EE, Gunzburg MJ, Nguyen TL, Howlett GJ, Rothacker J, Nice EC, Clayton AH, Mulvaney P. (2008) 'Experimental determination of quantum dot size distributions, ligand packing densities, and bioconjugation using analytical ultracentrifugation', Nano Letters, 8, 2883-2890.
- Binger KJ, Pham CL, Wilson LM, Bailey MF, Lawrence LJ, Schuck P, Howlett GJ. (2008) 'Apolipoprotein C-II amyloid fibrils assemble via a reversible pathway that includes fibril breaking and rejoining', J Mol Biol, 376, 1116-1129.
- Griffin MD, Mok ML, Wilson LM, Pham CL, Waddington LJ, Perugini MA, Howlett GJ. (2008) 'Phospholipid interaction induces molecular-level polymorphism in apolipoprotein C-II amyloid fibrils via alternative assembly pathways', J Mol Biol, 375, 240-256.
2007
- Wilson LM, MokYF, Binger KJ, Griffin MD, Mertens HD, Lin F, Wade JD, Gooley PR, Howlett GJ. (2007) 'A structural core within apolipoprotein C-II amyloid fibrils identified using hydrogen exchange and proteolysis', J Mol Biol, 366, 1639-1651.
- Stewart CR, Wilson LM, Zhang Q, Pham CL, Waddington LJ, Staples MK, Stapleton D, Kelly JW, Howlett, GJ. (2007) 'Oxidized cholesterol metabolites found in human atherosclerotic lesions promote apolipoprotein C-II amyloid fibril formation', Biochemistry, 46, 5552-5561.
- Stewart CR, Haw A,3rd, Lopez R, McDonald TO, Callaghan JM, McConville MJ, Moore KJ, Howlett GJ, O'Brien KD. (2007) 'Serum amyloid P colocalizes with apolipoproteins in human atheroma: functional implications', J Lipid Res, 48, 2162-2171.
- Legge FS, Treutlein H, Howlett GJ, Yarovsky I. (2007) 'Molecular dynamics simulations of a fibrillogenic peptide derived from apolipoprotein C-II', Biophys Chem, 130, 102-113.
- Gunzburg MJ, Perugini MA, Howlett GJ. (2007) 'Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E', J Biol Chem, 282, 35831-35841.
2006
- Wilson LM, Pham CL, Jenkins AJ, Wade JD, Hill AF, Perugini MA, Howlett GJ. (2006) 'High density lipoproteins bind Abeta and apolipoprotein C-II amyloid fibrils', J Lipid Res, 47, 755-760.
- Mok YF & Howlett GJ. (2006) 'Sedimentation velocity analysis of amyloid oligomers and fibrils', Methods Enzymol, 413, 199-217.
- Howlett GJ & Moore KJ. (2006) 'Untangling the role of amyloid in atherosclerosis', Curr Opin Lipidol, 17, 541-547.
- Howlett GJ, Minton AP, Rivas G. (2006) 'Analytical ultracentrifugation for the study of protein association and assembly', Curr Opin Chem Biol, 10, 430-436.
- Hill EK, Krebs B, Goodall DG, Howlett GJ, Dunstan DE. (2006) 'Shear flow induces amyloid fibril formation', Biomacromolecules, 7, 10-13.
2005
- Stewart CR, Tseng AA, Mok YF, Staples MK, Schiesser CH, Lawrence LJ, Varghese JN, Moore KJ, Howlett GJ. (2005) 'Oxidation of low-density lipoproteins induces amyloid-like structures that are recognized by macrophages', Biochemistry, 44, 9108-9116.
2004
- Medeiros LA, Khan T, El Khoury JB, Pham CL, Hatters DM, Howlett GJ, Lopez R, O'Brien KD, Moore KJ. (2004) 'Fibrillar amyloid protein present in atheroma activates CD36 signal transduction', J Biol Chem, 279, 10643-10648.
- MacRaild CA, Stewart CR, Mok YF, Gunzburg MJ, Perugini MA, Lawrence LJ, Tirtaatmadja V, Cooper-White JJ, Howlett GJ. (2004) 'Non-fibrillar components of amyloid deposits mediate the self-association and tangling of amyloid fibrils', J Biol Chem, 279, 21038-21045.
- MacRaild CA, Howlett GJ, Gooley PR. (2004) 'The structure and interactions of human apolipoprotein C-II in dodecyl phosphocholine', Biochemistry, 43, 8084-8093.