High resolution studies to examine the amyloid core and oligomeric intermediates

Lead Research Organisation: University of Sussex
Department Name: Sch of Life Sciences


Proteins are fundamental to almost every biological process in the body and usually adopt a specific three-dimensional structure in order to function. Occasionally, some proteins change their structure and misfold and this may lead to them aggregate or polymerise to form elongated fibres. This type of process is associated with a number of devastating diseases that include Alzheimer's and Parkinson's disease and Bovine spongiform encephalopathy (MSE or 'Mad Cow Disease'). In these diseases the process of misfolding appears to be linked to their progression. The aggregates are made of the body's own proteins and are called amyloid. These amyloid fibrils accumulate causing disruption to the surrounding body tissues. We are interested in what causes normally soluble protein to misfold and to aggregate. In order to understand this better, we are looking at the structure of the final aggregated form, the amyloid. This work is carried out using X-rays, electrons and computer processing. We are also looking at the process of aggregation using a number of different experimental techniques. The aim is to gain a clear picture of the architecture of the amyloid fibril and this will help to understand what causes the fibrils to form and why they are so stable. We can also start to design drugs that can bind and prevent fibril formation.

Technical Summary

Amyloid fibrils are highly ordered and stable aggregates of normally soluble proteins. These fibrous assemblies accumulate in a number of diseases known as the amyloidoses and now more broadly as the misfolding or conformational diseases. There are many proteins and peptides known to form amyloid fibrils in disease and in vitro. These share very little or no sequence homology, yet all form fibres that share common structural features. This infers that primary sequence is relatively unimportant. The fibrils are composed of hydrogen bonded beta-sheet structures and several beta-sheets are held together via side chain interactions. We postulate that the side chain composition of amyloid fibrils has a fundamental affect on the stability and efficiency of formation of the amyloid fibril. Our study focusses on the structural elucidation of core interactions within the amyloid fibril using a model peptide system. Using peptide design methods, we will explore how specific side chain residues contribute to fibril formation and eventual structural order with the fibrils. High-resolution X-ray and electron diffraction with electron microscopy will be used to examine the molecular architecture of the resulting assemblies. Highly ordered arrangements may yield stable structures with potential for use as biomaterials. This model system also provides an ideal opportunity to perform an in depth examination of the early structural intermediates and to probe the importance of primary sequence for their formation and toxicity.


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Description By studying a range of amyloidogenic peptides and also the Abeta peptide, we were able to show that primary sequence is linked to eventual structure. We revealed that the Abeta peptide is toxic to cells and accumulates in lysosomes and autophagosomes.
Exploitation Route We will continue to better understand amyloidogenesis
Sectors Healthcare

Description Since the work of this grant, we have developed a non-aggregation prone, non-toxic variant of Abeta which has been reported by publication and is covered by a patent. The peptide is currently being licensed to a company.
First Year Of Impact 2016
Sector Chemicals
Description Soap box science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Soap box science at Brighton Seafront to talk to the public about our research. Women in Science
Year(s) Of Engagement Activity 2017
URL http://soapboxscience.org/soapbox-science-2017-brighton/