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Structural Studies of Amyloid Fibrils and Oligomers

  • Author(s): Boyer, David Robert
  • Advisor(s): Eisenberg, David S
  • et al.
Abstract

Amyloid proteins play a critical role in both health and disease. Their unique fibrillar structure – termed the cross-β fold – is adopted by proteins ranging from the melanin-storing pre-melanosomal protein to the familiar amyloid-β plaques associated with Alzheimer’s Disease. Amyloid proteins also form smaller, non-fibrillar oligomers that are implicated in the pathology of numerous amyloid diseases. Despite years of effort to visualize the atomic structures of full-length amyloid proteins, their structures have evaded traditional structural biology techniques such as X-ray crystallography. It is only recently through the development of new techniques such as solid-state biomolecular NMR and cryo-electron microscopy with direct electron detectors that we have been able to visualize the atomic structures of amyloid fibrils. Using these techniques we can answer outstanding questions in amyloid structural biology such as, what are the stabilizing interactions in amyloid fibrils? What are the effect of hereditary mutations found in amyloid protein sequences on their fibril structures? Why do amyloid proteins only grow indefinitely in their length but not their width? What are the non-fibrillar, oligomeric structures of amyloid proteins? In this dissertation, I apply X-ray crystallography, cryo-electron microscopy, and computational structural analysis to answer these questions. In Chapter 2, I propose a model for previously unseen long-range interactions between the far N-terminus of the protein tau with the fibril core in Alzheimer’s Disease Paired Helical Filaments. In Chapters 3 and 4, I determine the structures of the amyloid fibrils of α-synuclein containing Parkinson’s Disease hereditary mutation H50Q and Lewy Body Dementia hereditary mutation E46K, respectively, to investigate the role of hereditary disease mutations in modulating α-synuclein fibril structure. In Chapter 5, I analyze all the known amyloid fibril structures determined by cryo-electron microscopy to date in order to show how the helical properties and unique fold of amyloid fibrils place an upper limit on the width of the fibrils, which blocks them from growing in directions other than the fibril axis. In Chapter 6, I study the pre-fibrillar, oligomeric particles of amyloid-β S26s – a modified form of the amyloid-β peptide found in the amyloid plaques of Alzheimer’s Disease – in order to understand what types of structures other than the cross-β fold could exist for non-fibrillar assemblies of amyloid proteins.

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