ZMBH - Open Positions

Scientific Job Openings

Project Title: Structure-function analysis of J-domain cochaperones

Project leader: Matthias P. Mayer

Application Deadline: until position is filled

Start of PhD project: as soon as possible

Source of Funding: University of Heidelberg

Project Description
In the center of this PhD project is the molecular mechanism of the Hsp70 chaperone machinery. Hsp70 chaperones are central hubs of the protein quality control network and work in collaboration with J-domain cochaperones and nucleotide exchange factors to facilitate a wide variety of protein folding processes and so (re)establish protein homeostasis. The Hsp70s are highly dynamic nanomachines that modulate the conformation of their substrate polypeptides by transiently binding to short, mostly hydrophobic stretches. This interaction is regulated by an intricate allosteric mechanism. The J-domain cochaperones target Hsp70 to their polypeptide substrates, and the nucleotide exchange factors regulate the lifetime of the Hsp70-substrate complexes. In vivo, Hsp70 and J-domain cochaperones are modified by posttranslational modifications and the aim of this PhD project will be to analyze the molecular mechanism J-domain proteins in vitro using biochemical and biophysical techniques with purified proteins. Complementary in-vivo-experiments will be carried out in E. coli and mammalian cell culture.

References:
Mayer, M.P. The Hsp70-chaperone machines in bacteria, Front Mol Biosci. (2021) Jun 7;8:694012. doi: 10.3389/fmolb.2021.694012
Mayer, M. P. & Gierasch, L. M. Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones. Journal of Biological Chemistry jbc.REV118.002810 (2018). doi:10.1074/jbc.REV118.002810
Kityk, R., Kopp, J. & Mayer, M. P. Molecular Mechanism of J-Domain-Triggered ATP Hydrolysis by Hsp70 Chaperones. Molecular Cell 69, 227–237.e4 (2018).
Kityk, R., Vogel, M., Schlecht, R., Bukau, B. & Mayer, M. P. Pathways of allosteric regulation in Hsp70 chaperones. Nat Commun 6, 8308 (2015).
Mayer, M. P. Hsp70 chaperone dynamics and molecular mechanism. Trends in Biochemical Sciences 38, 507–514 (2013).

Methods that will be used:
Molecular biology methods, Protein purification methods, biochemical assays, fluorescence spectroscopy and mass spectrometry; E. coli and mammalian cell culture.

Profile of candidate’s qualification:
The candidate should have a strong background in biochemistry/biophysics and should be highly motivated to succeed in science. Experience in mammalian cell culture would be an advantage.

Please send this form to the HBIGS office by email to: r.lutz@hbigs.uni-heidelberg.de

PhD position:
“Microtubules – building them at the right time, at the right place”

Centre for Molecular Biology (ZMBH)
Heidelberg University

Microtubules are highly dynamic polymers with essential functions in chromosome segregation in mitosis and meiosis, intracellular organization, cell motility and neurogenesis. Microtubules are targets for drugs that are used in cancer therapy (Paclitaxel and Vinca alkaloids). Microtubule malfunction is associated with cancer, infertility and neurological diseases.

Using gamma-tubulin complexes, cells have developed mechanisms for the assembly of microtubules from tubulin subunits. We just have resolved the high resolution cryo-EM structure of the large vertebrate gamma-tubulin ring complex (gamma-TuRC) composed of over 30 subunits (published in Nature 2019). Unexpectedly, we identified actin as a component of the gamma-TuRC. The activity of the gamma-TuRC is modulated in time and space by accessory factors, for example microtubule polymerases and activators such as the microcephaly protein CDK5RAP2.

In this project we aim to understand the role of actin in the gamma-TuRC, when and where regulatory co-factors play a role, how they impact the structure of the gamma-TuRC and how the activity of these regulators is changed in cancer and adapted in specific cell types, for example neurons.

The PhD student will be using a broad range of techniques such as cryo-electron microscopy, CRISPR/Cas9 technology for genomic knock-ins and knockouts and live cell imaging to study microtubule assembly.
The highly motivated PhD student should have a background in biochemistry or cell biology. 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 Heidelberg Biosciences International Graduate School (HBIGS) (http://www.hbigs.uni-heidelberg.de/). The PhD position is funded for 3 years

Please send applications (CV, motivation letter, two references, bachelor and master transcripts) to E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Relevant publications:

Liu P, Zupa E, Neuner A, Böhler A, Loerke J, Flemming D, Ruppert T, Rudack T, Peter C, Spahn C, Gruss OJ, Pfeffer S, Schiebel E (2019). Insights into the assembly and activation of the microtubule nucleator γ-TuRC. Nature. doi: 10.1038/s41586-019-1896-6. 
Gunzelmann J, Ruthnick D, Lin TC, Zhang W, Neuner A, Jakle U, Schiebel E (2018) The microtubule polymerase Stu2 promotes oligomerization of the gamma-TuSC for cytoplasmic microtubule nucleation. Elife 7: e39932
Lin TC, Neuner A, Flemming D, Liu P, Chinen T, Jakle U, Arkowitz R, Schiebel E (2016) MOZART1 and gamma-tubulin complex receptors are both required to turn gamma-TuSC into an active microtubule nucleation template. J Cell Biol 215: 823-840
Lin TC, Neuner A, Schiebel E (2015) Targeting of gamma-tubulin complexes to microtubule organizing centers: conservation and divergence. Trends Cell Biol 25: 296-307
Lin TC, Neuner A, Schlosser YT, Scharf AN, Weber L, Schiebel E (2014) Cell-cycle dependent phosphorylation of yeast pericentrin regulates gamma-TuSC-mediated microtubule nucleation. Elife 3: e02208
Gombos L, Neuner A, Berynskyy M, Fava LL, Wade RC, Sachse C, Schiebel E (2013) GTP regulates the microtubule nucleation activity of gamma-tubulin. Nat Cell Biol 15: 1317-27
Erlemann S, Neuner A, Gombos L, Gibeaux R, Antony C, Schiebel E (2012) An extended γ-tubulin ring functions as a stable platform in microtubule nucleation. J Cell Biol 197: 59-74
Knop M, Schiebel E (1998) Receptors determine the cellular localization of a γ-tubulin complex and thereby the site of microtubule formation. EMBO J 17: 3952-3967

Master Projects

in the laboratory of Prof. E. Schiebel, Centre for Molecular Biology (ZMBH), University of Heidelberg, Germany

My laboratory at the ZMBH, University of Heidelberg, is offering Master projects in the following areas:

The structure and function of gamma-tubulin complexes.  Gamma-tubulin complexes assemble microtubules from tubulin subunits. Microtubules have essential functions for chromosome segregation in mitosis and meiosis, fertility, transport process in particularly in neurons. Drugs such as Taxol that target tubulin are broadly used in cancer therapy. Gamma-tubulin complexes regulate the spatial and temporal formation of microtubules. In this project we determine the structure of gamma-tubulin complexes by Cryo-EM. We will also analyse how gamma-tubulin complexes interact with microtubule polymerases.

Centrosome duplication and centriole-centrosome conversion. Centrosomes are the main microtubule organizing centres in human cells. They only duplicate once per cell cycle. Misregulation of centrosome duplication triggers a p53 response and G1 arrest. This safeguard mechanism is bypassed in cancer cells. After duplication in S phase centrosomes convert into mature centrosomes. Here we analyse the molecular mechanism of this conversion process.

Centrosome cohesion. The two centrosomes of a cell are linked together into one unit from G1 until G2 phase. At the beginning of mitosis this linkage is resolved by the kinase NEK2. Here we will study molecular mechanisms of this linkage, the structure of the linker and functional consequences if centrosome cohesion fails.

Nuclear pore complex biogenesis and spindle pole body duplication. Nuclear pore complexes and the yeast spindle pole body (SPB; yeast microtubule organizing centre) are both embedded in the double membrane of the nuclear envelope. Here we aim to understand how large protein assemblies become inserted into the nuclear envelope and how the inner and outer nuclear envelopes fuse during this embedding process.

During the 6-month master project, you will receive a Student Assistant Contract (Hiwi contract).

Please send applications with a short motivation letter, CV, bachelor transcripts and the name of one referee to Prof. Dr. E. Schiebel (schiebel.elmar@zmbh.uni-heidelberg.de).

Lab Rotation in the Laboratory of Prof. Elmar Schiebel, ZMBH, Heidelberg University

My laboratory at the ZMBH, Heidelberg University, is offering lab rotations (6-8 weeks) for Master students who are interested in cell biology, molecular biology or biochemistry.

Topics are:

The structure and function of gamma-tubulin complexes.  Gamma-tubulin complexes assemble microtubules from tubulin subunits. Microtubules have essential functions for chromosome segregation in mitosis and meiosis, fertility, transport process in particularly in neurons. Drugs such as Taxol that target tubulin are broadly used in cancer therapy. Gamma-tubulin complexes regulate the spatial and temporal formation of microtubules. In this project we determine the structure of gamma-tubulin complexes by Cryo-EM.

Genomic tagging of genes in human cells. Presently we are establishing and optimizing approaches based on gRNA and Cas9-like enzymes to tag human genes at the 3’ and 5’ end with a toolbox of PCR cassettes (NeonGreen, GFP, mRuby, auxin degron tag). This allows tagging of human genes within 20 days.

Centrosome duplication and centriole-centrosome conversion. Centrosomes are the main microtubule organizing centres in human cells. They only duplicate once per cell cycle. Misregulation of centrosome duplication triggers a p53 response and G1 arrest. This safeguard mechanism is bypassed in cancer cells. After duplication in S phase centrosomes convert into mature centrosome. Here we analyse the molecular mechanism of the conversion process.

Nuclear pore complex biogenesis and spindle pole body duplication. Nuclear pore complexes and the yeast spindle pole body (SPB; yeast microtubule organizing centre) are both embedded in the double membrane of the nuclear envelope. Here we aim to understand how large protein assemblies become inserted into the nuclear envelope and how the inner and outer nuclear envelopes fuse during this embedding process.

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

BIOINFORMATICS POSTDOC IN EVOLUTIONARY GENOMICS

Center for Molecular Biology (ZMBH), Heidelberg University, Germany

A postdoctoral position (3 years with possible extensions) is available immediately in the evolutionary genomics group of Henrik Kaessmann.

We are seeking highly qualified and enthusiastic applicants with strong skills in computational biology/bioinformatics, ideally also with experience in data mining and comparative or evolutionary genome analyses.

We have been interested in a range of topics related to the origins and evolution of vertebrate organs. In the framework of our research, we generate and analyze comprehensive genomics (e.g., RNA-seq, ATAC-seq) datasets based on samples from our large organ collections. More recently, we have begun to bring the work of our lab to the level of single cells using state-of-the-art single-cell genomics technologies and bioinformatics procedures.

The postdoctoral fellow will be funded by a recently awarded ERC Advanced Grant. In the framework of this grant, we seek to unravel the cellular and molecular origins and evolution of the vertebrate brain.The fellow will perform integrated evolutionary/bioinformatics analyses based on extensive single-cell transcriptomic and epigenomic data produced in our lab for species representing all major vertebrate lineages, ranging from jawless vertebrates such as the sea lamprey to mammals such as platypus. The precise project will be developed together with the candidate.

In our lab, we attach great importance to a highly collaborative and positive team spirit! And we are particularly fond of the diverse cultural backgrounds of our lab members, which contribute to a very enriching atmosphere.

The language of our institute is English and its members form a highly international group. The ZMBH is located in Heidelberg, a picturesque international city next to the large Odenwald forest and Neckar river. The city offers a very stimulating, diverse and collaborative research environment, with the European Molecular Biology Laboratory (EMBL), German Cancer Research Center (DKFZ), Heidelberg Institute of Theoretical Studies (HITS), and the Max Planck Institute for Medical Research located in close proximity to the University.

For more information on the group and our institute more generally, please refer to our website at the ZMBH (http://www.zmbh.uni-heidelberg.de/Kaessmann/).

Please submit a CV, statement of research interest, and names of three references to: Henrik Kaessmann (h.kaessmann@zmbh.uni-heidelberg.de).

Selected publications:

Sarropoulos, I., Sepp, M., Frömel, R., Leiss, K., Trost, N., Leushkin, E., Okonechnikov, K., Joshi, P., Giere, P., Kutscher, L.M., Cardoso-Moreira, M., Pfister, S.M., and Kaessmann, H. (2021) Developmental and evolutionary dynamics of cis-regulatory elements in mouse cerebellar cells.Science. doi: 10.1126/science.abg4696. URL.

Mazin, P.V., Khaitovich, P., Cardoso-Moreira, M., and Kaessmann, H. (2021) Alternative splicing during mammalian organ development. Nat. Genet. doi: 10.1038/s41588-021-00851-w. URL

Wang, Z.Y., Leushkin, E., Liechti, A., Ovchinnikova, S., Mößinger, K., Brüning, T., Rummel, C., Grützner, F., Cardoso-Moreira, M., Janich, P., Gatfield, D., Diagouraga, B., de Massy, B., Gill, M.E., Peters, A.H.F.M., Anders, S., and Kaessmann, H. (2020) Transcriptome and translatome co-evolution in mammals. Nature 588: 642-647.

Cardoso-Moreira M., Halbert, J., Valloton, D., Velten, B., Chen, C., Shao, Y., Liechti, A., Ascenção, K., Rummel, C., Ovchinnikova, S., Mazin, P.V., Xenarios, I., Harshman, K., Mort, M., Cooper, D.N., Sandi, C., Soares, M.J., Ferreira, P.G., Afonso, S., Carneiro, M., Turner, J.M., VandeBerg, J.L., Fallahshahroudi, A., Jensen, P., Behr, R., Lisgo, S., Lindsay, S., Khaitovich, P., Huber, W., Baker, J., Anders, S., Zhang, Y.E., and Kaessmann H. (2019) Gene expression across mammalian organ development. Nature 571: 505-509.

Sarropoulos, I., Marin, R., Cardoso-Moreira, M., and Kaessmann, H. (2019) Developmental dynamics of lncRNAs across mammalian organs and species. Nature 571: 510-514.

Cortez, D., Marin, R., Toledo-Flores, D., Froidevaux, L., Liechti, A., Waters, P.D., Grutzner, F., and Kaessmann, H. (2014) Origins and functional evolution of Y chromosomes across mammals. Nature 508: 488-493.

Necsulea, A., Soumillon, M., Warnefors, M., Liechti, A., Daish, T., Zeller, U., Baker, J.C., Grutzner, F., and Kaessmann, H. (2014) The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature 505: 635-640.

Brawand, D., Soumillon, M., Necsulea, A., Julien, P., Csardi, G., Harrigan, P., Weier, M., Liechti, A., Aximu-Petri, A., Kircher, M., Albert, F.W., Zeller, U., Khaitovich, P., Grutzner, F., Bergmann, S., Nielsen, R., Paabo, S., and Kaessmann, H. (2011) The evolution of gene expression levels in mammalian organs. Nature 478: 343-348.

Non-Scientific Job Openings

Additional positions for research assistants and non-scientific personnel are also regularly published on the pages of the University's central job market:

Central job market of the University