Project No.2269

Primary Supervisor

Dr Wei-Feng Xue – University of Kent

Co-Supervisor(s)

Prof Louise C Serpell – University of Sussex

Summary

Amyloid fibrils are diverse structures formed by many different protein sequences.

They are highly polymorphic, meaning polypeptide chains of identical amino acid sequences under identical conditions are capable of self-assembly into a spectrum of different fibril structures. Amyloid may provide essential biological functions but also abnormally accumulate in numerous human diseases such as Alzheimer’s and Parkinson’s diseases. The structural 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 structural polymorphs is essential to decipher the precise links between amyloid structures and their biological functions and disease associated properties such as toxicity, strains, propagation and spreading. Work in the Xue and Serpell labs has led to developments in atomic force microscopy (AFM) imaging methodologies that demonstrated exciting new potential of AFM to achieve 3D structural reconstruction. This project will develop new integrative structural biology methodologies involving AFM together with cryogenic electron microscopy (cryo-EM) data to enable detailed characterisation of the extent of structural polymorphism in disease associated amyloid-beta, tau and alpha-synuclein sequences. Detailed AFM image data sets from which 3D reconstruction of individual filaments assembled from the protein sequences will be produced. Distinctive fibril polymorphs will then be classified. These data will shed light on the assembly landscape of amyloid filament assembly and provide molecular and mechanistic information on amyloid polymorphism. In this project, the successful PhD candidate will be trained in a range of areas including computational biology (structural modelling and bioinformatics), biochemistry (chromatography, molecular biology, protein chemistry) and biophysics (atomic force microscopy, x-ray fibre diffraction, kinetics).