Development of Yeast Prionomics

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

Intellectual Merit: Self-assembled fibrous protein aggregates (amyloids) probably represent an ancient protein fold. Seeded polymerization of an amyloid provides a basis for potential infectivity or heritability of an amyloid state. Indeed, recent evidence demonstrates that ability to form transmissible amyloids (prions) is widespread among yeast proteins, and likely among the proteins from other organisms. It is no longer possible to ignore the potential input of prions in inheritance and evolution. However, understanding of the biological roles of yeast prions remains at rudimentary levels, in part due to the lack of sequence- and phenotype-independent approaches for prion detection and monitoring. Overall goal of this research is to compose the yeast prionome, that is, a catalogue of proteins capable of forming prions in their native state, and to assess impact on yeast biology and evolution. This will help to determine if prion profiles of the yeast strains are driven by natural selection in the same way as genotypic patterns are. For this purpose, approaches for prion detection are being developed that are independent of strain genotype and applicable to the high throughput analysis and prion profiling. Specific research objectives are as follows: 1) to optimize the sequence-independent biochemical approaches for rapid prion detection; 2) to characterize new prion candidates. Intellectual merit is driven by the emphasis on a rapidly emerging topic of protein-based inheritance (that is still grossly understudied and may significantly change our understanding of biological evolution). New unbiased biochemical tools for prion detection are being developed and applied to important biological questions, such as identification of new prions, characterization of their effects, and determining of the complete prion profiles of the yeast strains. Broader Impacts: Biochemical approaches and tools for detection of amyloids and prions are potentially amenable to high throughput analysis and can be applied to characterizing prionomes of yeast and other organisms in their natural environments. This will open a whole new area of environmental "prionomics", providing a complement to environmental genomics, and may have far-reaching implications for understanding the biological roles of amyloids and the processes that have been hypothesized to involve prion-like switches, such as memory, protection from stresses, and assembly of intracellular structures. New amyloid detection tools, developed in the course of this project, and data on the connection between the sugar utilization and prions could be of interest to the biotechnological industry. This project heavily relies on participation of students and will be tightly integrated with the educational process by providing subjects of study for Ph.D. dissertations and for teaching undergraduate and graduate courses. The PI's lab participates in the interdisciplinary centers focused on macromolecular assemblies and molecular evolution, and these centers will significantly benefit from the success of the project.