Structural polymorphism of amyloidogenic peptides

Marshall, Karen Elizabeth (2010) Structural polymorphism of amyloidogenic peptides. Doctoral thesis (DPhil), University of Sussex.

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The folding of a protein from a linear chain of amino acids into its functional native state is one of the most widely investigated yet enigmatic events to take place in the natural world. An ever‐increasing number of proteins and peptides are known to fold, or “misfold”, into protease‐resistant amyloid fibrils that share a common cross‐β structure, despite having no apparent sequence homology. Self‐assembly of particular proteins or peptides into amyloid is believed to be the molecular basis of many diseases, including Alzheimer's Disease, Type II diabetes and the transmissible spongiform encephalopathies. More recent evidence suggests a functional, non‐pathogenic role for amyloid in certain organisms, which has inspired its use as a biomaterial. In order to understand these diseases and exploit amyloid for industrial use using a bottom‐up design approach, detailed knowledge of the assembly process and structure of amyloid is required. Many short peptides are known to assemble into amyloid‐like fibres in vitro that have very similar properties to those formed in vivo. These “model systems” can give deeper insight into what triggers, drives and influences self‐assembly. Furthermore, they can provide more detailed structural information than is often obtained from larger amyloid‐forming proteins. Using two short peptides (the yeast prion fragment GNNQQNY and the designed peptide KFFEAAAKKFFE), which form amyloid-like microcrystals that have been structurally characterised previously, the roles of particular residues in assembly and structure were investigated. Results reveal that aromatic residues are fundamental determinants of assembly and may contribute to polymorphic propensity. Furthermore, non‐aromatic sequence changes can have dramatic effects on fibril morphology both at a macromolecular level and in the underlying peptide packing arrangement. Structural variations were found between amyloid‐like fibres and microcrystals formed from the same peptide, which has implications for how to examine amyloid structure in the future. The balance of conditions required for proteins or peptides to adopt specific conformations is very fine. Polymorphism may be an inherent property of amyloidogenic proteins and peptides and detailing the structural intricacies of each form will be essential from both a biomedical and industrial perspective

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry
Depositing User: Library Cataloguing
Date Deposited: 12 Aug 2010
Last Modified: 10 Aug 2015 14:21
Google Scholar:38 Citations

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