UCLA

The conversion of human proteins into the highly ordered fibrillar aggregates known as amyloid fibrils is implicated in a wide range of diseases. The number of proteins known to exhibit this activity is constantly growing and the molecular mechanisms that lead to amyloid aggregation are not fully understood. I focus on genetic mutations as a mechanism by which to predict novel amyloidogenic proteins. I also examine how mutations can explain some structural features of amyloid fibrils formed by mutant proteins. I developed a computational method for predicting previously unknown amyloidogenic proteins by calculating the propensity of disease mutations to induce amyloid aggregation. This method, called Identification of Mutations Promoting Amyloidogenic Transitions (IMPAcT), identified protein TFG as a novel amyloidogenic protein. I biochemically validated the amyloidogenic nature of mutant protein TFG and determined the structures of the mutant amyloid fibrils, demonstrating the direct and indirect influence of each mutation on the structure and stability of the fibrils. Lastly, I composed a literature review of the mechanisms by which mutations drive the conversion to an amyloid fibril and influence the resulting molecular structures. This body of research expands our understanding of amyloid proteins and opens avenues for further study of the relationship between genetics and amyloids.This dissertation includes three supplementary files. Chapter 2 has two supplementary spreadsheets: Table S2-1 is a spreadsheet containing information regarding all the candidate mutations identified by the IMPAcT method; Table S2-2 is a spreadsheet containing the results of a statistical test on patterns in the kinds of mutations which were predicted to be amyloidogenic by the IMPAcT method. Chapter 4 has one supplementary spreadsheet: Table S4-1 is a spreadsheet containing relevant information on all pathogenic amyloid proteins considered in the review.