(BBSRC DTP) Elucidating the responses to nascent protein misfolding and aggregation stress

The aim of this study is to characterize the proteins that aggregate during nascent protein misfolding and to investigate how cells mitigate the damaging effects of aggregate formation. Protein aggregation is the abnormal association of misfolded proteins which have the potential to form larger aggregate structures that tend to be insoluble. There has been relatively little work aimed at identifying the different molecular species involved in protein aggregation and their relationship to cellular toxicity. In principle, all proteins can aggregate particularly if they become misfolded or denatured, exposing hydrophobic surfaces which have a greater propensity to associate and aggregate. We know very little about the kinetics of protein aggregation, or the defence systems which mitigate the toxic consequences of aggregate formation. There is also much debate on whether these protein aggregates serve protective roles via sequestration of misfolded proteins, or alternatively, are they detrimental to cells via loss of available functional proteins.

This project aims to determine how and why nascent proteins aggregate in cells in order to understand the role of aggregation in cellular homeostasis and protein production. The starting point for this project is our recent finding that the Tsa1 peroxiredoxin is required to protect against reactive oxygen species (ROS) which are generated as a result of the formation of protein aggregates. Peroxiredoxins (Prx’s) are ubiquitous thiol-specific proteins that have multiple functions in stress protection, including protection against oxidative stress. This project focusses on the yeast Tsa1 Prx which is a member of the highly conserved 2-Cys Prx enzyme family. We have localized Tsa1 with protein aggregates and proposed that it specifically acts to protect against the toxicity of mitochondrial ROS generation during widespread protein aggregation. Identifying and characterizing the regulatory mechanisms that control protein aggregation and production will benefit industrial researchers, interested in maximising protein production from biological systems for biotechnological and biopharmaceutical applications.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.