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

Project leader:

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

Project description:

Title:
Regulation of protein degradation through SHRED
Summary:
This project is an opportunity to explore the molecular mechanism, physiological roles and evolutionary conservation of SHRED, a novel pathway regulating protein degradation.

Cells are able to selectively eliminate proteins that are damaged or no longer needed. However, this process needs to be carefully controlled so that the right proteins are destroyed at the right time. Inefficient protein turnover during aging causes neurodegeneration. Similarly, cancer cells often suffer from chronic stress and need efficient protein degradation to survive. Therefore, understanding how protein degradation is regulated may allow us to activate or inhibit it for therapeutic intervention.

We have recently discovered a novel regulatory cascade in yeast that helps to specify the targets of protein degradation. Various environmental stresses induce the synthesis of the previously uncharacterized protein Roq1, which is proteolytically cleaved and reprograms substrate recognition by the ubiquitin ligase Ubr1. This reprogramming accelerates the degradation of misfolded proteins by the proteasome. We have named this pathway SHRED, for stress-induced homeostatically regulated protein degradation. Intriguingly, SHRED also breaks down native, well-folded proteins, suggesting functions beyond ridding the cell of damage. The aims of this project are to (1) elucidate the precise molecular mechanism of SHRED through biochemical in vitro reconstitution, (2) identify the endogenous substrates and physiological roles of SHRED in yeast, and (3) determine if SHRED is conserved in mammals.
References:
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, in press.

For more information, please visit www.zmbh.uni-heidelberg.de/schuck.
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.
Keywords:
Protein quality control and degradation; stress responses