Wei-Feng Xue, University of Kent
Louise Serpell, University of Sussex
Amyloid fibrils are highly polymorphic structures formed by many different protein sequences. They provide biological functions but also abnormally accumulate in numerous human diseases such as Alzheimer’s and Parkinson’s diseases. The physical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To understand the fundamental origins of fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. This project will produce a systematic series of short peptide sequences originating from a range of disease associated and functional amyloidogenic proteins, designed with systematically varied amino acid sequences and peptide length. Employing gentle, force-curve based AFM will then produce detailed image data sets from which 3D reconstruction of individual filaments assembled from the peptide sequences can be produced using state-of-the-art methodologies developed in the host laboratory. Distinctive fibril polymorphs will then be classified, and sample heterogeneity will be quantified. The sequencestructure and sequence-polymorphism relationships of amyloid fibril assembly will then be deciphered. These data will shed light on the mechanistic origin of amyloid polymorphism, and provide important information regarding the energy landscape of amyloid filament assembly.