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Inhibiting protein-protein interactions in the early stages of amyloid formation


Project Description

Amyloidosis is a pathological condition associated with the aggregation of proteins into fibrils. Despite the importance of amyloid diseases in today’s society, therapies remain remote, due to a lack of understanding of some of the fundamental molecular processes involved.
In this project we will use directed evolution, biochemistry, native mass spectrometry and other biophysical assays, to develop new inhibitors of amyloid formation and to determine their mechanism of action in structural detail. In parallel, cell biology will be used to determine whether ligands that bind the proteins of interest also inhibit cytotoxicity. The project will focus on amylin (IAPP), involved in type II diabetes, and A involved in Alzheimer’s disease, two of the major diseases challenging today’s society and for which there are currently no effective therapeutics on the market.

The student employed will learn a variety of skills in this multi-disciplinary project that, together, will open the door to new understandings of how and why amyloid fibril formation kills cells and whether small molecules can ameliorate or even inhibit this deadly process.

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.

Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.

There are 2 stages to the application process. Please see our website for more information: View Website

References

FS:
Konijnenberg, A., Ranica, S., Narkiewicz, J., Legname, G., Grandori, R., Sobott*, F., Natalello*, A. (2016) Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein. Anal Chem. 88, 8468.
Konijnenberg, A., Sobott, F. (2015) Bouncing off the walls: excited protein complexes tell their story. Chem. Biol 22, 583.
Lermyte, F., Sobott, F. (2015) Electron transfer dissociation provides higher-order structural information of native and partially unfolded protein complexes. Proteomics, 15, 2813.
Konijnenberg, A., Yilmaz, D., Ingólfsson, H.I., Dimitrova, A., Marrink, S.J., Lid, Z., Vénien-Bryan, C., Sobott*, F., Koçer*, A. (2014) Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry.
PNAS, 111, 17170. (* co-corresponding authors)

SER:
Saunders, J.C., Young, L.M., Mahood, R.A., Revill, C.H., Foster, R.J., Jackson, M.P., Smith, D.A.M., Ashcroft, A.E., Brockwell, D.J. & Radford, S.E. (2016) An in vivo platform for identifying inhibitors of protein aggregation Nature Chem. Biol., 12, 94-101
Stull, F., Koldewey, P., Humes, J.R., Radford, S.E. & Bardwell, J.C.A. (2016) Substrate protein folds while it is bound to the ATP-independent chaperone Spy Nat. Struct. Mol. Biol. 1, 53-59
Young, L.M., Saunders, J.C., Mahood, R.A., Revill, C.H., Foster R.J., Tu, L.-H., Raleigh, D.P., Radford, S.E. & Ashcroft, A.E. (2015) Screening and classifying small molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. Nature Chemistry, 1, 73-81
Tipping, K.W., Karamanos, T.K., Jakhria, T., Iadanza, M.G., Goodchild, S.C., Tuma, R., Ranson, N.A., Hewitt, E.W. & Radford, S.E. (2015) pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. PNAS, 112, 5691-5696

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