Ruprecht-Karls-Universität Heidelberg
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Schuck0118 - Scientist (f/m) / PhD position
Project no:

Project leader:

Project supervisor:
Schuck, Sebastian
Application deadline:
30. Sep 2018
Start of PhD project:
1. Nov 2018

Project description:

Protein quality control and cell adaptation to stress
This project is an opportunity to explore SHRED, a novel pathway regulating protein degradation during stress.

Cells eliminate damaged proteins as part of protein quality control. This ability is essential for cell adaptation to stress, and failure to destroy the right proteins at the right time leads to disease. For example, inefficient protein degradation during aging causes disorders such as Alzheimer’s. Similarly, cancer cells chronically accumulate misfolded proteins and only survive by degrading them. Therefore, activating or inhibiting protein degradation may help combat many diseases. For this, a key step is to understand the mechanisms by which cells regulate protein degradation.

We have recently discovered SHRED (stress-induced homeostatically regulated protein degradation), a novel regulatory pathway in yeast that specifies the targets of protein degradation (Szoradi et al., Molecular Cell, 2018). Stress induces the synthesis of the protein Roq1, which is proteolytically cleaved and reprograms the ubiquitin ligase Ubr1 for accelerated degradation of misfolded proteins. The aims of this project are to elucidate the molecular mechanism of SHRED through biochemical in vitro reconstitution, identify the physiological roles of SHRED in yeast, and determine if SHRED exists in mammals.
Szoradi, T, Schaeff K, … and Schuck S. SHRED is a regulatory cascade that reprograms Ubr1 substrate specificity for enhanced protein quality control during stress. Molecular Cell, 2018.

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Methods that will be used:
The in vitro reconstitution of SHRED will involve the purification of recombinant proteins, biochemical ubiquitination assays and cryo-electron microscopy. The analysis of SHRED functions will involve yeast as a model organism, genetic screening approaches, and biochemical as well as flow cytometric protein degradation assays. The search for mammalian SHRED will involve mammalian tissue culture, protein affinity purification, and a bit of luck.
Cooperation partners:
Bernd Bukau, Michael Knop, Marius Lemberg (all ZMBH)
Personal qualifications:
Are you passionate about understanding life’s fascinating complexity at the molecular level? If so, our young lab in a lively, international and collaborative research environment may be the right place for you. A strong background in biochemistry or molecular cell biology is essential for this project. Also, you should be comfortable working in an English-speaking environment.
Protein quality control and degradation; stress responses