Targeted protein degradation in nuclear quality control condensates

1 PhD project offered in the IPP winter call 2022

Scientific Background

Targeted protein degradation can be enhanced by compartmentalizing protein degradation through the formation of liquid-liquid phase-separated proteolytic centers in the cell. Proteolytic centers in the nucleus contain proteasome and proteasome-associated proteins as well as components of the ubiquitin system and proteasome shuttle proteins. In these proteolytic centers defective proteins and unassembled subunits of protein complexes accumulate before their degradation. Moreover, proteolytic centers might be particularly relevant during conditions that challenge protein and organelle homeostasis, which can result in overload of the ubiquitin–proteasome system and autophagy. The formation of these proteolytic membrane-less condensates appears to be driven by multivalent, weak interactions between proteasome shuttle proteins and poly-ubiquitin chains, especially those that are branched. It remains largely unknown which stress conditions trigger the formation of nuclear proteolytic centers and how they are resolved. Which proteins are targeted to and are subsequently degraded in these condensates and what are the underlying molecular mechanisms? What are the biophysical and chemical principles that govern phase separation induced the components of these condensates? Answering these questions would bring us a major step forward in understanding how cells respond to proteotoxic stress, which role phase separation plays in protein homeostasis and its underlying biophysical mechanisms as well as how its malfunctioning can lead to neurological disease.

PhD Project: “Deciphering substrate selection by nuclear proteolytic condensates and the biophysical properties that drive their formation”

In this project, you will be associated with the Luck lab and will work closely together with a co-funded second PhD student situated in the Beli group at IMB and a co-funded postdoctoral researcher in the Kukharenko and Kremer labs at the MPI for Polymer Research in Mainz. The specific aims of this PhD project are to first decipher how proteins are selected and recruited for degradation to the nuclear, proteolytic centers under proteotoxic stress conditions focusing on selected factors. To this end the PhD candidate will use novel protein interaction interface prediction tools developed in the Luck lab as well as medium throughput protein interaction assays, biochemical, and biophysical laboratory methods to validate predictions. Second, the PhD candidate will work in close collaboration with the postdoctoral researcher from the polymer field to delineate the mechanisms of phase separation of the nuclear proteolytic condensates and to study their role in the response to proteotoxic stress. Here, primarily protein biochemistry and biophysical in vitro assays as well as HTP imaging and fluorescence techniques will be employed. We seek for a PhD candidate with basic expertise in programming and data analysis as well as cell and molecular biology techniques. Experience in protein biochemistry is a plus. The candidate should have a strong interest in the biological processes that are subject to this study and bring a high collaborative spirit. We offer working in a young, motivated, and dynamic team of researchers in a highly interdisciplinary environment with a good work-life balance.

If you are interested in this project, please select Luck (Nuclear Quality Control) as your group preference in the IPP application platform.

Publications relevant to this project

Heidelberger et al EMBO Rep 2018 https://doi.org/10.15252/embr.201744754
Martinez-Noel et al JMB 2018 https://doi.org/10.1016/j.jmb.2018.01.021
Berg et al PLoS Comp Biol 2018 https://doi.org/10.1371/journal.pcbi.1006589
Luck et al Nature 2020 https://doi.org/10.1038/s41586-020-2188-x
Zhao et al J Phys Chem 2020 https://doi.org/10.1021/acs.jpcb.0c01949

Contact

Dr. Katja Luck
Email
Webpage: www.imb.de/luck
                 www.imb.de/beli
                 www.mpip-mainz.mpg.de/en/kremer