Unscrambling the Egg: The Biochemistry and Cell Biology of Protein Aggregation

Prof Daniel Raleigh (primary)
UCL SMB
University College London, Institute of Structural and Molecular Biology
Dr. Konstantinos Thalassinos (secondary)
UCL SMB
nstitute of Structural and Molecular Biology

Abstract

Protein aggregation plays a central role in a wide range of fields, from biotechnology, to human health and physiology, but the process is not understood at the molecular level and the cellular consequences are often confusing. Elucidating the features which govern protein aggregation is a central problem in structural biology and cell biology. Using the pancreatic hormone amylin, as a model system, the PhD student will conduct interdisciplinary research involving state of the art mass spectrometry assays together with biochemical and cell biology measurements to quantitatively relate specific conformational features of the protein to its tendency to aggregate.


References

1. Raleigh, D. P., Zhang, X., Hastoy, B., Clark, A. (2017) Amylin the beta-ell Assassin Journal of Molecular Endocrinology (2017) 59, R121–R140. DOI: 10.1530/JME-17-0105

2. Akter, R., Cao, P., Noor, H., Ridgway, Z., Tu, L. H., Wang, H., Wong, A. G., Zhang, X. X. et al (2016) Islet Amyloid Polypeptide: Structure, function, and pathophysiology Jour. Diabetes Research, Article Number, 2798269. DOI: 10.1155/2016/2798269

3. Abedini, A., Cao, P., Plesner, A., Zhang, J. He, M., Derk, J., Patil, S. A., Rosario, R., et al (2018) RAGE binds pre-amyloid IAPP intermediates and mediates pancreatic beta cell proteotoxicity. Jour. Clinical Invest. 128, 682-698. DOI: 10.1172/JCI85210

4. Abedini, A., Plesner, A., Cao, P., Ridgway, Z., Zhang J., Tu LH, Middleton CT, Chao, B., Sartori, D. J., Meng, F., et al. 2016 Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics. eLife 5, e12977. DOI:10.7554/eLife.12977

5. Sivalingam, G. N., Cryar, A., Williams, M. A., Gooptu, B., and Thalassinos, K., (2018). Deconvolution of ion mobility mass spectrometry arrival time distributions using a genetic algorithm approach: Application to alpha(1)-antitrypsin peptide binding. International Journal of Mass Spectrometry 426: 29-37. DOI: 10.1016/j.ijms.2018.01.008.

6. Nyon, M.P., Prentice, T., Day, J., Kirkpatrick, J., Sivalingam, G. N., Levy, G., Haq, I., Irving, J. A., Lomas, D.A., Christodoulou, J., Gooptu, B., and Thalassinos, K., (2015) An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of alpha1-antitrypsin upon ligand binding. Protein Science, 24: 1301-1312. DOI: 10.1002/pro.2706.

7. Serrano, A. L., Lomont, J. P., Tu, L.-H., Raleigh, D. P., and Zanni, M. T. (2017) A free energy barrier caused by the refolding of an oligomeric intermediate controls the lag time of amyloid formation by hIAPP. J. Am. Chem. Soc. 139, 16748−16758. DOI: 10.1021/jacs.7b08830

8. Zhang, X., St Clair, J. R., London, E. and Raleigh, D. P. Islet Amyloid Polypeptide membrane interactions: Effects of membrane composition (2017) Biochemistry, 56, 376-390. DOI: 10.1021/acs.biochem.6b01016

9. Watson, M. D., Peran, I., Zou, J., Bisel, O., Raleigh, D. P. (2017) Selenomethionine quenching of tryptophan fluorescence provides a simple probe of protein structure. Biochemistry 56, 1085-1094. DOI: 10.1021/acs.biochem.6b01000

10. Akter, R., Abedini, A., Ridgway, Z., Kleinberg, J., Schmidt, A. M, and Raleigh, D. P (2017). Evolutionary adaptation and amyloid formation: Does the reduced amyloidogenicity and cytotoxicity of ursine amylin contribute to the metabolic adaption of bears and polar bears? Israeli J. Chem. 57, 750-761. DOI: 10.1002/ijch.201600081


BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
Cell BiologyStructural Biology
Techniques & Approaches
BiochemistryBiophysicsChemistryMolecular Biology