Virtually all cellular functions are executed by proteins. The synthesis of a functional protein encompasses many complex processes: translation, folding into an appropriate three-dimensional structure, (in many cases) assembly into a macromolecular complex, and localization to a specific cellular compartment. Mistakes can occur during any of these steps, resulting in a myriad of different defective protein species. Moreover, many proteins are susceptible to damage by endogenous and environmental stresses, given the dynamic and often unstable nature of protein structures. It is therefore no wonder that roughly 10% of the proteome mass is dedicated to the life cycle of proteins. The proteostasis network is estimated to comprise ∼2,000 factors that act in concert to maintain the fitness of the proteome, including molecular chaperones and their regulatory co-factors, quality-control factors such as E3 ubiquitin ligases, and degradation machineries such as the ubiquitin–proteasome and autophagy–lysosome systems. Importantly, maintaining the correct protein fold is important not only to avoid loss-of-function effects, but also the formation of potentially toxic protein aggregates that represent a hallmark of many aging-associated neurodegenerative diseases.
Our group is broadly interested in the following questions:
Ribosome-associated quality control (RQC) is a conserved eukaryotic pathway that removes nascent polypeptide chains from ribosomes that stalled during translation. The key component of this pathway, the E3 Ubiquitin ligase Listerin/Ltn1, first came into attention when a mouse genetic screen showed that a partial loss-of-function mutation in the LTN1 gene causes a profound neurodegenerative phenotype. Since then, considerable advances been made towards mechanistically characterizing the components of the RQC pathway. Interestingly, it has been shown that stalled nascent chains can be extended with non-templated c-terminal Alanine and Threonine residues (CAT tails). These extensions have been suggested to promote stalled nascent chain degradation by two mechanisms: increasing chances of Listerin-mediated ubiquitination by exposing Lysine residues initially buried in the ribosomal exit tunnel, or by assuming a “degron” function, i.e., marking proteins for proteasomal degradation once they are released from the ribosome. However, CAT tails can also self-associate and form insoluble aggregates that can disrupt the proteostasis network, highlighting the importance of proper clearance of stalled nascent chains.
Most insights into RQC came from the analysis of artificial model substrates containing specific ribosomal-stalling sequences. The most potent stalling sequence characterized so far consists in long stretches of AAA codons (circa 20 or more), which encode for poly(Lys) chains. Translation of these sequence can naturally occur when the mRNA’s poly(A) tail is erroneously inserted inside the coding sequence, rather than at the 3’ UTR. Apart from this situation, little is known about the natural causes of ribosomal stalling and RQC-mediated degradation.
Some of the questions we want to address:
We are based at the Center for Molecular Medicine Cologne (CMMC), a central autonomous research and educational center located at the heart of the Life Science Campus at the University of Cologne (UoC), Germany. The institute provides administrative infrastructure, modern laboratories, as well as access to a number of core facilities (https://www.cmmc-uni-koeln.de/core-facilities/overview) that offer not only state-of-the-art equipment, but also training and support with data analysis. Research on campus encompasses a wide range of molecular, genetic and "omics" approaches using various model organisms and unique disease models. Therefore, our team has all the tools and the support needed to pursue any scientific question that becomes of interest. Moreover, one of CMMC’s strengths is to bring together research scientists and clinicians in order to foster interdisciplinary collaboration from the laboratory to the clinic, creating unique opportunities for translational research.
The CMMC building is located within walking reach to many internationally recognized institutes, such as the Cologne Center for Genomics, Max Planck Institute for Metabolism Research, Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), and the Max-Planck Institute for Biology of Ageing. Notably, Cologne is one of the world-leading places for aging research. Since our main topic of investigation – proteostasis – represents one of the pillars of aging, we are well integrated in this environment. This means not only numerous possibilities for collaboration, but also a thriving scientific environment with an abundant offer of lectures in our interest range.
PhD students in our lab will have the opportunity to join a structured graduate program, such as the Interdisciplinary Program Molecular Medicine (IPMM) and the Graduate School for Biological Sciences (GsfBS). These programs foster career development through scientific and soft skills training, advanced method courses, networking opportunities, systematic guidance, and administrative support. We are happy to provide our students with a solid platform to advance their careers.
Last but not least, Cologne is a vibrant, cosmopolitan city located at the heart of Europe. It is the fourth-most populous city in Germany, having more than 30% of its residents coming from abroad. Moreover, Cologne has numerous cultural opportunities, strong visual arts and cinema, theatre, opera, orchestra, jazz and live music scene. It is truly a fun-loving city, epitomized by its world famous Carnival festivities. Our English-speaking lab is eager to get into the spirit of the city and to welcome scientists from any nationality.
For further information, please visit www.cmmc-uni-koeln.de