Ruprecht-Karls-Universität Heidelberg
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Lemberg0118 - Scientist (f/m) / PhD position
Project no:
Lemberg0118

Project leader:

Project supervisor:
Lemberg, Marius
Application deadline:
31. Dec 2018
Start of PhD project:
1. Feb 2019

Project description:

Title:
Function of the Presenilin-type intramembrane protease SPP in regulation of membrane protein homeostasis
Summary:
Regulated intramembrane proteolysis is an evolutionarily conserved mechanism that is involved in diverse cellular processes such as transcription control and growth factor secretion. Recently, we and others have found that intramembrane proteolysis is also involved in the control of membrane protein homeostasis. The main question we are addressing is how membrane proteins that are either damaged or not needed by the cell at certain conditions are removed without affecting other proteins and the overall integrity of cellular organelles. Within this context, our main focus is to analyze how intramembrane proteases and their catalytically inactive homologues target selected membrane proteins for regulated degradation. For most of our research we use mammalian tissue culture cells as a model system, but we have also established related projects in budding yeast.

Our previous work has identified and characterized two non-canonical arms of the endoplasmic reticulum (ER) associated protein degradation (ERAD) machinery that involve the rhomboid protease RHBDL4 and presenilin-type protease SPP and identified the mitochondrial rhomboid PARL as a key regulator of mitophagy. When deregulated, these central cellular homeostasis mechanisms have been connected to neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Also, our work on budding yeast has identified a conserved ERAD mechanism for the SPP homologue Ypf1, defining a role of intramembrane proteolysis in the control of nutrient metabolism. Please visit our lab page for more information: http://www.zmbh.uni-heidelberg.de/lemberg/default.shtml

In this proposed PhD project, we aim to follow up on our recent proteomics-based substrate identification analysis and define the physiological role of the presenilin-type intramembrane protease SPP as a key regulator of ER homeostasis. Moreover, by using a combination of cell-free systems and tissue culture cells, we aim to decipher the molecular mechanism of SPP function and its regulation.
References:
Avci D. and Lemberg M.K. (2018) Membrane Protein Dislocation by the Rhomboid Pseudoprotease Dfm1: No Pore Needed? Mol. Cell 69, 161-162.
Avci D. and Lemberg M.K. (2015) Clipping or Extracting: Two ways for membrane protein degradation. Trends Cell Biol. 25, 611-622.

Avci D. et al. and Lemberg M.K. (2014) The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance. Mol. Cell 56, 630-640.

Chen C. et al. and Lemberg M.K. (2014) Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u. EMBO J 33, 2492-2506.

Lemberg M.K. and Martoglio B. (2002) Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol. Cell 10: 735-744.
Weihofen A., Binns K., Lemberg M.K., Ashman K., Martoglio B. (2002) Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296: 2215-2218.
Methods that will be used:
CRISPR/Cas9-mediated gene editing, super-resolution microscopy, proteomics, lipidomics, cell biology, molecular biology, and membrane biochemistry.
Cooperation partners:
Britta Brügger (BZH), ZMBH proteomics and imaging core facilities.
Personal qualifications:
We are looking for a highly motivated PhD student who holds a Master degree in biology or biochemistry. Expertise in membrane protein biochemistry and proteomics are of advantage.

The successful candidate will be part of a very collaborative research team. Weekly progress report meetings 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 core facilities. Our staff is international and the working language is English.
Keywords:
Regulated intramembrane proteolysis, protein quality control, neurodegenerative disease