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Scientific Job Openings

 
Listed 22.5.18  

PhD position “Protein quality control and cell adaptation to stress“

The laboratory of Sebastian Schuck is looking for a PhD student 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, in press). 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, identify the physiological roles of SHRED in yeast, and determine if SHRED exists in mammals.

If you are passionate about understanding life’s fascinating complexity at the molecular level, our young lab in a lively, international and collaborative research environment may be the right place for you. If interested, please visit our website for more information (http://www.zmbh.uni-heidelberg.de/Schuck) and submit your application through the HBIGS programme (Heidelberg International Biosciences Graduate School, http://www.hbigs.uni-heidelberg.de).

 
Listed 11.4.18  

PhD position: “Nuclear pore complex biogenesis
Centre for Molecular Biology (ZMBH)
Heidelberg University

The nuclear pore complex (NPC) is a large cylindrical structure with multiple copies of over 30 different proteins named nucleoporins (NUPs). The NPC is embedded in the nuclear envelope (NE) at fusion sites of the inner and outer nuclear membrane where it facilitates nuclear-cytoplasmic transport of RNA and proteins. NPCs assemble in the intact nuclear envelope (interphase human cells or yeast cells with a closed mitosis) by an inside-out mechanism. NUPs become deposited from within the nucleus to the inner nuclear membrane, deform this membrane and eventually the inner and outer nuclear membranes fuse. We recently have identified with Brr6 and Brl1 two conserved integral membrane proteins that may play a role in nuclear membrane fusion during NPC biogenesis.

In this project we will study NPC biogenesis using budding yeast and human cells as model systems. The PhD student will use biochemical approaches (Brr6 and Brl1 reconstitution into liposomes), super resolution microscopy (SIM and STED), electron microscopy, CRISPR/Cas9 technology and live cell imaging to study NPC assembly.
Highly motivated PhD students with a background in biochemistry, cell biology or molecular biology should apply. Successful candidates will be part of an international team of PhD students and postdocs that works at the forefront of scientific research. The PhD student will be a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (http://www.hbigs.uni-heidelberg.de/).

The PhD position (TV-L E13 (part-time)) is funded for 3 years.
Time period: June/July 2018 – May/June 2021
Please send applications to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Mailing address: Prof Elmar Schiebel, ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany

Please understand that received applications cannot be returned. In case of same aptitude, priority employment for handicapped people.

For literature on this topic, please follow this link to our website:
http://www.zmbh.uni-heidelberg.de/schiebel/open.html

 

 
Listed 11.4.18  

PhD position: “Role of Human Ubiquitin-like ISG15 in Cell Regulation and Cancer Development”
Centre for Molecular Biology (ZMBH)
Heidelberg University

The Interferon-Stimulated Gene 15 product, ISG15, modifies proteins in a similar manner to ubiquitin. ISG15 appears to play important roles in various biological and cellular functions including innate immunity, cell adaptation to actin defects and DNA damage. In addition, overexpression of ISG15 has been shown to contribute to metastatic abilities of certain breast cancer cell lines suggesting that ISG15 promotes tumor formation. However, relative to ubiquitin, substrates of ISG15 and the molecular consequences of this conjugation are still poorly understood. Recently, we have identified the human Ras GTPase-activating-like protein IQGAP1, a scaffold protein that interacts with RAC1 and CDC42, as an ISG15 substrate. ISGylation of IQGAP1 has an impact on the interaction of RAC1 and CDC42 with IQGAP1 and the activity of these GTPases.
In this project we will identify substrates of ISG15 by affinity purification and mass spectrometry-based approaches and identify the proteins that recognize ISGylated proteins. We will study the consequences of substrate ISGylation for normal cell growth and in malignancy. ISG15 substrates will be analysed using CRISPR/Cas9 knockin and knockout strategies.
Highly motivated PhD students with a background in cell biology or molecular biology should apply. Successful candidates will be part of an international team of PhD students and postdocs that works at the forefront of scientific research (http://www.cell.com/developmental-cell/meet-the-author/berati-cerikan). The PhD student will be a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (http://www.hbigs.uni-heidelberg.de/).

The PhD position (TV- L E13 (part-time)) is funded for 3 years.
Time period: June/July 2018 –May/June 2021
Please send applications to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Mailing address: Prof Elmar Schiebel, ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany

Please understand that received applications cannot be returned. In case of same aptitude, priority employment for handicapped people.

For literature on this topic, please follow this link to our website:
http://www.zmbh.uni-heidelberg.de/schiebel/open.html

 

 
Listed 11.4.18  

PhD position: “Centrosome duplication
Centre for Molecular Biology (ZMBH)
Heidelberg University

The centrosomes is the main microtubule organizing centre of human cells. As DNA centrosomes duplicate once per cell cycle. Malfunction of centrosome duplication is a hallmark of cancer cells and recent data suggest that centrosome overamplificaiton contributes to cell transformation. In addition, lack of centrosomes or to many centrosomes causes chromosome missegregation and p53 activation leading to cell cycle arrest in G1.

In this project we will study cell cycle dependent centrosome duplication and steps leading to centrosome maturation in G2 and mitosis. The PhD student will use biochemical approaches, super resolution microscopy (STED), electron microscopy, CRISPR/Cas9 technology and live cell imaging to study centrosome duplication in untransformed and cancer cells.
Highly motivated PhD students with a background in biochemistry, cell biology or molecular biology should apply. Successful candidates will be part of an international team of PhD students and postdocs that works at the forefront of scientific research. The PhD student will be a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (http://www.hbigs.uni-heidelberg.de/).

The PhD position (TV-L E13 (part-time) is funded for 3 years.
Time period: June/July 2018 – May/June 2021
Please send applications to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Mailing address: Prof Elmar Schiebel, ZMBH, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany

Please understand that received applications cannot be returned. In case of same aptitude, priority employment for handicapped people.

For literature on this topic, please follow this link to our website:
http://www.zmbh.uni-heidelberg.de/schiebel/open.html

 
Listed 11.4.18  

PhD position: “Nuclear pore complex biogenesis
Centre for Molecular Biology (ZMBH)
Heidelberg University

The nuclear pore complex (NPC) is a large cylindrical structure with multiple copies of over 30 different proteins named nucleoporins (NUPs). The NPC is embedded in the nuclear envelope (NE) at fusion sites of the inner and outer nuclear membrane where it facilitates nuclear-cytoplasmic transport of RNA and proteins. NPCs assemble in the intact nuclear envelope (interphase human cells or yeast cells with a closed mitosis) by an inside-out mechanism. NUPs become deposited from within the nucleus to the inner nuclear membrane, deform this membrane and eventually the inner and outer nuclear membranes fuse. We recently have identified with Brr6 and Brl1 two conserved integral membrane proteins that may play a role in nuclear membrane fusion during NPC biogenesis.

In this project we will study NPC biogenesis using budding yeast and human cells as model systems. The PhD student will use biochemical approaches (Brr6 and Brl1 reconstitution into liposomes), super resolution microscopy (SIM and STED), electron microscopy, CRISPR/Cas9 technology and live cell imaging to study NPC assembly.
Highly motivated PhD students with a background in biochemistry, cell biology or molecular biology should apply. Successful candidates will be part of an international team of PhD students and postdocs that works at the forefront of scientific research. The PhD student will be a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (http://www.hbigs.uni-heidelberg.de/). The PhD position is funded for 3 years.

Please send applications to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Relevant recent publications:

1          Zhang, W. et al. Brr6 1 and Brl1 locate to nuclear pore complex assembly sites to promote their biogenesis. J Cell Biol in press (2018).
2          Ruthnick, D. et al. Characterization of spindle pole body duplication reveals a regulatory role for nuclear pore complexes. J Cell Biol 216, 2425-2442, doi:10.1083/jcb.201612129 (2017).
3          Rüthnick, D. & Schiebel, E. Duplication of the yeast spindle pole body once per cell cycle. Mol Cell Biol 36, 1324-1331, doi:10.1128/MCB.00048-16 (2016).
4          Seybold, C. et al. Kar1 binding to Sfi1 C-terminal regions anchors the SPB bridge to the nuclear envelope. J Cell Biol 209, 843-861, doi:10.1083/jcb.201412050 (2015).

 
Listed 11.4.18  

PhD position: “Role of Human Ubiquitin-like ISG15 in Cell Regulation and Cancer Development”
Centre for Molecular Biology (ZMBH)
Heidelberg University

The Interferon-Stimulated Gene 15 product, ISG15, modifies proteins in a similar manner to ubiquitin. ISG15 appears to play important roles in various biological and cellular functions including innate immunity, cell adaptation to actin defects and DNA damage. In addition, overexpression of ISG15 has been shown to contribute to metastatic abilities of certain breast cancer cell lines suggesting that ISG15 promotes tumor formation. However, relative to ubiquitin, substrates of ISG15 and the molecular consequences of this conjugation are still poorly understood. Recently, we have identified the human Ras GTPase-activating-like protein IQGAP1, a scaffold protein that interacts with RAC1 and CDC42, as an ISG15 substrate. ISGylation of IQGAP1 has an impact on the interaction of RAC1 and CDC42 with IQGAP1 and the activity of these GTPases.
In this project we will identify substrates of ISG15 by affinity purification and mass spectrometry-based approaches and identify the proteins that recognize ISGylated proteins. We will study the consequences of substrate ISGylation for normal cell growth and in malignancy. ISG15 substrates will be analysed using CRISPR/Cas9 knockin and knockout strategies.
Highly motivated PhD students with a background in cell biology or molecular biology should apply. Successful candidates will be part of an international team of PhD students and postdocs that works at the forefront of scientific research (http://www.cell.com/developmental-cell/meet-the-author/berati-cerikan). The PhD student will be a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (http://www.hbigs.uni-heidelberg.de/). The PhD position is funded for 3 years.
Please send applications to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Relevant publications from our laboratory:

Cerikan, B., R. Shaheen, G.P. Colo, C. Gläßer, S. Hata, K.-P. Knobeloch, F.S. Alkuraya, R. Fässler, and E. Schiebel. (2016). Cell intrinsic adaptation arising from chronic ablation of a key Rho GTPase regulator. Dev. Cell, 39:28-43.

Cerikan B. and E. Schiebel. (2017). Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases. Small GTPases, 23:1-8.

Chen, N.-P., B. Uddin, R. Hardt, W. Ding, M. Panic, I. Lucibello, P. Kammerer, T. Ruppert and E. Schiebel. (2017). Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm. Proc. Natl. Acad. Sci. U S A, 114:5201-5206.

Chen, N.-P., B. Uddin, R. Voit, and E. Schiebel. (2016). Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion. Proc. Natl. Acad. Sci. USA, 113:990-995.

 
Listed 11.4.18  

PhD position: “Centrosome duplication
Centre for Molecular Biology (ZMBH)
Heidelberg University

The centrosomes is the main microtubule organizing centre of human cells. As DNA centrosomes duplicate once per cell cycle. Malfunction of centrosome duplication is a hallmark of cancer cells and recent data suggest that centrosome overamplificaiton contributes to cell transformation. In addition, lack of centrosomes or to many centrosomes causes chromosome missegregation and p53 activation leading to cell cycle arrest in G1.

In this project we will study cell cycle dependent centrosome duplication and steps leading to centrosome maturation in G2 and mitosis. The PhD student will use biochemical approaches, super resolution microscopy (STED), electron microscopy, CRISPR/Cas9 technology and live cell imaging to study centrosome duplication in untransformed and cancer cells.
Highly motivated PhD students with a background in biochemistry, cell biology or molecular biology should apply. Successful candidates will be part of an international team of PhD students and postdocs that works at the forefront of scientific research. The PhD student will be a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (http://www.hbigs.uni-heidelberg.de/). The PhD position is funded for 3 years.

Please send applications to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Relevant publications:

1-51       Mardin, B. R., Agircan, F. G., Lange, C. & Schiebel, E. Plk1 Controls the Nek2A-PP1gamma Antagonism in Centrosome Disjunction. Curr Biol 21, 1145-1151, doi:S0960-9822(11)00605-1 [pii]
10.1016/j.cub.2011.05.047 (2011).
2          Mardin, B. R. et al. EGF-induced centrosome separation promotes mitotic progression and cell survival. Dev Cell 25, 229-240, doi:S1534-5807(13)00161-5 [pii]
10.1016/j.devcel.2013.03.012 (2013).
3          Mardin, B. R. et al. Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nat Cell Biol 12, 1166-1176, doi:ncb2120 [pii]
10.1038/ncb2120 (2010).
4          Mardin, B. R. & Schiebel, E. Breaking the ties that bind: New advances in centrosome biology. J Cell Biol 197, 11-18, doi:jcb.201108006 [pii]
10.1083/jcb.201108006 (2012).
5          Rüthnick, D. & Schiebel, E. Duplication of the yeast spindle pole body once per cell cycle. Mol Cell Biol 36, 1324-1331, doi:10.1128/MCB.00048-16 (2016).

 
Listed 16.1.18  

PhD student position:
Cryo-EM analysis of the co-translational machinery for protein folding and maturation in prokaryotes

Background:
Co-translational folding and maturation of proteins require an intricate network of folding chaperones and processing enzymes that act on the growing nascent protein in a co-translational manner. Structural information on ribosome-nascent chain-chaperone complexes is sparse, because the involved interactions are mostly transient, labile and possibly highly flexible. This renders the involved assemblies inaccessible to classical reductionist structural biology approaches that rely on extensive biochemical purification and require conformationally homogenous particle populations for averaging. We consequently pursue a different approach and image these processes using cryo electron tomography (cryo-ET)-based strategies, which can reveal the three-dimensional arrangement of individual macromolecules even in crowded native microenvironments at molecular resolution and therefore render extensive biochemical purification unnecessary. This approach allows us to analyze the three-dimensional spatial distribution of ribosomes, chaperones and processing enzymes for individual native polysomal assemblies under conditions that preserve the labile and transient interactions governing co-translational protein folding and maturation.

The project:
The central objective of this project will be to study defined polysomal assemblies engaged in the synthesis of model substrates in prokaryotic organisms. Cryo-ET approaches will be used to visualize these assemblies in both a non-cellular context and in sections of vitrified unperturbed cells obtained using focused ion beam (FIB) milling.

Methods that will be used:
High-resolution cryo electron microscopy and tomography approaches; advanced image processing; standard biochemical, molecular and cell biology methods

The candidate:
We are looking for a highly motivated PhD student holding a Master’s degree in life sciences with a strong background in computational biology. Experience in electron microscopy is of advantage, but not required.

Contact address:
pfeffer@biochem.mpg.de

 
Listed 16.1.18  

PhD student position:
Cryo-EM analysis of the co-translational machinery for protein folding and maturation in eukaryotes

Background:
Co-translational folding and maturation of proteins require an intricate network of folding chaperones and processing enzymes that act on the growing nascent protein in a co-translational manner. Structural information on ribosome-nascent chain-chaperone complexes is sparse, because the involved interactions are mostly transient, labile and possibly highly flexible. This renders the involved assemblies inaccessible to classical reductionist structural biology approaches that rely on extensive biochemical purification and require conformationally homogenous particle populations for averaging. We consequently pursue a different approach and image these processes using cryo electron tomography (cryo-ET)-based strategies, which can reveal the three-dimensional arrangement of individual macromolecules even in crowded native microenvironments at molecular resolution and therefore render extensive biochemical purification unnecessary. This approach allows us to analyze the three-dimensional spatial distribution of ribosomes, chaperones and processing enzymes for individual native polysomal assemblies under conditions that preserve the labile and transient interactions governing co-translational protein folding and maturation.

The project:
The central objective of this project will be to study defined polysomal assemblies engaged in the synthesis of model substrates in eukaryotic organisms. Cryo-ET approaches will be used to visualize these assemblies in both a non-cellular context and in sections of vitrified unperturbed cells obtained using focused ion beam (FIB) milling.

Methods that will be used:
High-resolution cryo electron microscopy and tomography approaches; advanced image processing; standard biochemical, molecular and cell biology methods

The candidate:
We are looking for a highly motivated PhD student holding a Master’s degree in life sciences with a strong background in computational biology. Experience in electron microscopy is of advantage, but not required.

Contact address:
pfeffer@biochem.mpg.de

 
Listed 29.3.16  

Postdoctoral positions are available in the Joazeiro laboratory.

Research in the laboratory investigates the function of E3 ubiquitin ligases in biology and disease (Deshaies & Joazeiro, 2009. Annu Rev Biochem. 78:399-434). The positions available are to elucidate the mechanism of action of the Listerin/Ltn1 E3 ligase in ribosome-associated protein quality control, and/or to understand how defects in Listerin function cause neurodegeneration.

We had previously reported on a new mouse model of ALS/motor neuron disease caused by mutation of Listerin, whose function was unknown at the time (Chu et al. 2009. PNAS 106:2097-103). Listerin is conserved in eukaryotes, so we utilized S. cerevisiae to study its function and found that this E3 is associated with the large ribosomal subunit and mediates quality control of aberrant nascent polypeptides (Bengtson & Joazeiro 2010. Nature 467:470-3; Lyumkis et al 2014. PNAS 111:15981-6).

Our research team undertakes different approaches to study the Listerin pathway, including biochemistry, yeast genetics, structural biology, mammalian tissue culture, and gene-disease association studies using ALS patient samples. We are also well positioned to uncover novel molecular mechanisms underlying neurodegeneration by applying the discoveries we make with these approaches to studies involving the Listerin-mutant mouse model.

The candidate is expected to be proactive and productive, and should have strong background in biochemistry and molecular biology.

Please send CV, a paragraph on current and future research interests, and the names and contact information of three references to Claudio Joazeiro (c.joazeiro@zmbh.uni-heidelberg.de).

 
Listed 24.11.2017  

2 PhD positions available: “Protecting protein homeostasis in neurodegenerative disease models by modulating the Hsp70/co-chaperone network”
The gradual accumulation and intercellular spreading of pathological α-synuclein (α-Syn) and tau is a hallmark of many neurodegenerative diseases, commonly referred to as synucleinopathies and tauopathies, respectively. Molecular chaperones function in folding and degradation of misfolded proteins and thus constitute a natural line of defence. Intriguingly, the disruption of cellular protein homeostasis due to aggregation of α-Syn and tau are a common pathogenic feature of these diseases, indicating that there might be common as well as unique sets of molecular chaperones protecting cells from these aggregation-prone proteins. This study aims to implement an integrated approach, combining complementary methodologies and model systems, ranging from in vitro biochemistry to mammalian cell culture to Caenorhabditis elegans to discover and investigate the mode of action of individual and shared components of the Hsp70/co-chaperone network(s) that are able to prevent aggregation, seeding, spreading and toxicity of misfolded α-Syn and tau. The ultimate goal is to identify potential drug targets that may help to prevent the progression of neurodegenerative diseases.
This project is supported by the German Federal Ministry of Education and Research (BMBF) under the aegis of the EU Joint Programme - Neurodegenerative Disease Research (JPND, www.jpnd.eu), as part of a multinational research project within the Call for ‘Pathway Analysis across Neurodegenerative Diseases’. Cooperation partners in France, The Netherlands and Sweden will contribute to this project.
Methods: C. elegans behavioral assays, mammalian cell culture, protein biochemistry, fluorescence microscopy, FRAP, FRET, electron microscopy, RNAi, protein solubility assays, western blotting, molecular cloning, generation of transgenic lines using CRSPR/Cas9 genome editing, RT-PCR, RT-QuIC, fluorescence anisotropy, spectroscopic approaches, immunofluorescence
Personal qualification: Masters (or equivalent) degree in life sciences, with a strong background in cell biology, biochemistry and genetics. Highly motivated to work in an international environment. Previous experiences with the methods that will be utilized is preferential, but not essential. The PhD students will be members of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS, http://www.hbigs.uni-heidelberg.de/).
Project leaders: Nussbaum, Carmen & Bukau, Bernd
How to apply: Applications are handled by HBIGS. All applications must be submitted via the online system (http://www.hbigs.uni-heidelberg.de/main_application.html) and refer to project no: Bukau_Nussbaum0117. Application deadline: 31. Dec 2017; Start of PhD projects: approx. 01. Mar 2018.
References:           
- Reviews:              
1. Nussbaum-Krammer CI et al. Caenorhabditis elegans as a model system for studying non-cell-autonomous mechanisms in protein-misfolding diseases. Dis Model Mech. 2014
2. Goedert M. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein. Science. 2015.
3. Nillegoda NB et al. Metazoan Hsp70-based protein disaggregases: emergence and mechanisms. Front Mol Biosci. 2015
- Original publications:
1. Rampelt H et al. Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO J. 2012
2. Nussbaum-Krammer CI et al. Spreading of a prion domain from cell-to-cell by vesicular transport in Caenorhabditis elegans. PLoS Genet. 2013
3. Nussbaum-Krammer CI et al. Investigating the spreading and toxicity of prion-like proteins using the metazoan model organism C. elegans. J Vis Exp. 2015
4. Gao X et al. Human Hsp70 Disaggregase Reverses Parkinson's-Linked α-Synuclein Amyloid Fibrils. Mol Cell. 2015
5. Nillegoda NB et al. Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature. 2015

 

 
 


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