Ruprecht-Karls-Universit├Ąt Heidelberg
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Lemberg0217 - Scientist (f/m) / PhD position
Project no:
Lemberg0217

Project leader:

Project supervisor:
Lemberg, Marius
Application deadline:
30. Nov 2017
Start of PhD project:
1. Jan 2018

Project description:

Title:
The role of rhomboid proteases in membrane protein quality control
Summary:
As the main entry point of the secretory pathway, the Endoplasmic Reticulum (ER) harbors complex quality control machinery that targets damaged and misfolded proteins into ER-associated degradation (ERAD). Similar checkpoints exist for the inner nuclear membrane, mitochondria, the Golgi compartment, and the late secretory pathway. A fundamental challenge is to understand how damaged membrane proteins are recognized and extracted from the lipid bilayer such that the rest of the organelle remains unaffected. While most of our understanding of ERAD comes from the p97-mediated dislocation of full-length substrates, we previously showed that the ubiquitin-dependent rhomboid protease RHBDL4 cleaves certain membrane proteins with unstable transmembrane helices thereby facilitating their degradation. However, the physiological function of RHBDL4 and how it is related to classical ERAD remains unclear. In order to allow physiological conclusions, we have established proteomic techniques to identify endogenous substrates. The continuous central objective of this project will be to decipher the molecular function of RHBDL4 and to define the conserved role of rhomboid proteases in the control of membrane protein homeostasis and stress response. We expect that our comprehensive analysis of rhomboid proteases will identify native substrates and regulatory principles in membrane protein homeostasis and stress response.
References:
Wunderle et al. & Lemberg (2016). Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGF-alpha. Sci. Rep. 6: 27342.

Avci & Lemberg (2015) Clipping or Extracting: Two ways for membrane protein degradation. Trends Cell Biol. 25, 611-622.

Fleig et al. & Lemberg (2012) Ubiquitin-Dependent Intramembrane Rhomboid Protease Promotes ERAD of Membrane Proteins. Mol. Cell 47, 558-569.
Methods that will be used:
CRISPR/Cas9-mediated gene editing, proteomics, cell biology, molecular biology, and membrane biochemistry
Cooperation partners:
Various groups in the SFB 1036 (http://www.zmbh.uni-heidelberg.de/sfb1036/)
Personal qualifications:
We are looking for a highly motivated PhD student who hold a Master degree in biology or biochemistry. Expertise in membrane biochemistry and proteomics are of advantage.

The successful candidate will be part of a very collaborative reach team. Weekly progress reports, and journal clubs ensure a challenging, yet helpful environment, in which the candidates will broaden their theoretical and practical knowledge and independent investigative thinking skills. Our Institute offers an internationally competitive research environment with access to excellent facilities. Our staff is international and the working language is English.
Keywords:
Regulated intramembrane proteolysis, protein quality control