Control of Heritable Protein Aggregation

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

This project will investigate how physiological changes regulate protein-based inheritance in yeast. Protein-based heritable elements (prions), particularly in fungi, are novel genetic elements that produce heritable changes in their host cells without any change in the DNA of their genes. This effect is achieved by switching between protein conformations (termed isoforms) one of which (the prion isoform) is able to reproduce itself by inducing other molecules of the same protein to switch into the same (prion) isoform. This project looks specifically at how these transitions are aided by another class of proteins, termed molecular chaperones, whose normal function is to promote correct protein folding and prevent protein misfolding. Understanding the physiological control of protein-based inheritance has a potential impact on the industrial use of yeast and other fungi. The research is integrated with course development, teaching and mentoring, thus assuring educational benefits in the areas of genetics, biochemistry and bionanotechnology. The research team includes both men and women graduate and undergraduate students, and a diverse team will be deliberately maintained. This project will also help to strengthen research infrastructure by contributing to the development of interdisciplinary centers at Georgia Institute of Technology. The main objective of this project is to uncover the pathway connecting the protein synthesizing ribosomal machinery to the cellular apparatus of heritable protein aggregation. The unifying hypothesis is that the ribosome-associated chaperone complex serves as a sensor of physiological changes and mediates effects of such changes on heritable protein-based elements (prions). This provides a new mechanism for physiology and the environment to influence the hereditary constitution of the cell and organism. The project uses yeast as a model system and employs a combination of genetic, biochemical and proteomic techniques, including newly developed approaches for aggregate detection, potentially applicable beyond yeast.