Prions are the basis of several fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans, mad cow disease in cattle, and scrapie in sheep. In yeast, prions have been found to underlie several non-Mendelian phenotypes. Despite differences in sequence, yeast prions share similar features with human prions including infectivity, prion strain phenomenon, and species barrier. Therefore, yeast prions are excellent model systems to study the mechanism of prion diseases. Several key aspects of human prion diseases are unambiguously illustrated using yeast prions, including the protein only hypothesis, conformational variations as the basis of prion strains, and involvement of chaperones. A knowledge gap in the prion field is the lack of detailed high-resolution structures for prion fibrils. In this project, we aim to determine fibril structures of he yeast prion protein Ure2, one of the best studied yeast prions, under quiescent and agitated conditions. It has been proposed that different fibril structures are the basis of different prion strains. Our preliminary studies have shown that Ure2 fibrils indeed adopt different structures under quiescent and agitated conditions. Full- atom structural models of Ure2 fibrils under these two conditions will bring insights into the structural basis of prion strains and mechanism of prio propagation. This project consists of three specific aims.
In Aim 1, we will determine the ?-strand and turn/loop regions in Ure2 fibril under quiescent and agitated conditions.
In Aim 2, we will obtain an extensive set of inter-residue distance constraints for quiescent and agitated Ure2 fibrils.
In Aim 3, we will use the experimental constraints and structure prediction program Rosetta to calculate atomic- level structure models for quiescent and agitated Ure2 fibrils.

Public Health Relevance

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a family of fatal neurodegenerative disorders that affect both humans and animals. Infection of prion diseases from consumption of beef has been a major public health concern and has huge economic impact. This project will provide insight into the mechanism of prion diseases using yeast prions as a model system and will help the development of effective therapeutics to treat human prion diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM110448-01
Application #
8673596
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gu, Lei; Liu, Cong; Stroud, James C et al. (2014) Antiparallel triple-strand architecture for prefibrillar A?42 oligomers. J Biol Chem 289:27300-13