Molecular basis for amyloid diseases.

摘要

There are at least 25 diseases that are associated with amyloid fibrils. The atomic structure(s) of amyloid fibrils remains an unanswered question in the field of structural biology.; The focus of my Ph.D. has been to understand better the molecular basis of amyloid fibril formation.; In Chapter 2 of my dissertation, I discuss our work on Ribonuclease A (RNase A) and the role of domain swapping in amyloid fibril formation. We have shown that amyloid-like fibrils formed from polyglutamine-inserted RNase A contain domain-swapped molecules with a native-like fold. Based on our data, we propose that the polyglutamine-RNase A amyloid is composed of a beta-sheet core formed from the polyglutamine insert decorated by globular domains with a domain-swapped, native-like fold.; In Chapter 3, I examine the fibril-forming propensity of the RNase A protein following the insertion of different fibril-forming peptides. Our results suggest that RNase A mutants containing different peptide inserts have different fibril-forming propensities, dependent both on the length and sequence of the inserted peptide.; In Chapter 4, I describe the structure of a fibril-forming peptide in the N-terminal hinge-loop region of RNase A. I also discuss why wild-type RNase A does not form amyloid-like fibrils in spite of containing a fibril-forming peptide.; In Chapter 5, I describe our studies on the Alzheimer's amyloid, Abeta. I discuss three crystal structures from the C-termini of Abeta1-40 and Abeta1-42 and the implications these structures have for the behavior of their longer parent peptides, Abeta1-40 and Abeta1-42. I also discuss the implications that the structures have for the atomic basis of strain variation in Abeta.; In chapter 6, I focus on the tau protein that forms neurofibrillary tangles in Alzheimer's disease and tauopathies. I have focused on the C-terminal repeat region of tau that has been proposed to form the beta-sheet core in the neurofibrillary tangles. I describe the crystal structure of a fibril-forming peptide that has been proposed to be part of the tau beta-sheet core and also describe ongoing studies on another fibril-forming peptide as well as longer constructs from the repeat region.