The Project
Cells face constant threats including microbial invasion, proteotoxic and organellar stress. Giant ubiquitin E3 ligases form the frontline of cellular defence, acting as colossal molecular machines that detect danger signals and neutralize threats by tagging unwanted molecules for removal. Despite their central role in innate immunity and cellular homeostasis, these mega-enzymes remain among the most poorly understood components of the ubiquitin system, being too large and flexible for predictive modelling, yet too complex for conventional structural approaches. This combination of biological impact, mechanistic mystery and technical challenge makes them exceptional study systems.
We are looking for a postdoctoral researcher to investigate how giant E3 ligases act as guardians against diverse cellular stresses. Key questions include: How do they recognize macro-substrates such as microbial epitopes, damaged organelles and RNA–protein condensates? How do they coordinate ubiquitination of non-canonical substrates, including lipids, sugars, and RNA, and what happens downstream? And how do disease mutations alter their activity to drive cancer, metabolic or autoimmune disorders?
About the Group
Our group explores unconventional degradation pathways located in the “dark corners” of ubiquitin signalling - mechanisms often dismissed as niche or technically challenging. Following this route, we discovered protein arginine phosphorylation as a bacterial degron, developed BacPROTAC antibiotics against drug-resistant mycobacteria and determined the first structures of giant E3 ligases including HUWE1, RNF213, BIRC6 and UBR4. Furthermore, we showed that ATP serves as a danger signal directing RNF213 against bacterial invaders and that ZNFX1 ubiquitinates and compacts RNA into RNPs to control antiviral immunity. Together, these discoveries set the stage for the next challenge: understanding how giant E3 ligases extend ubiquitin signalling beyond proteins and control it across diverse cellular stress pathways.
To explore this uncharted ubiquitin territory, we will combine cryo-EM, XLMS, proteomics, in vitro reconstitution, chemical biology, protein design and cellular assays, with cryo-ET looming at the horizon. A particular strength is our expertise in working with E3 mega-complexes that remain inaccessible to predictive tools such as AlphaFold3, making direct experimental investigation both necessary and rewarding.
About the Place
The IMP is part of the Vienna BioCenter, one of the world's leading life science campuses. It offers access to state-of-the-art cryo-EM infrastructure, proteomics, imaging, high performance computing and a vibrant interdisciplinary community. Our lab is part of the "Ubiquitin & Friends" network, a local proteostasis hub comprising more than 100 researchers across twelve Vienna BioCenter groups, fostering collaboration and innovation.
Your Profile
We are looking for a curious, ambitious, and collaborative scientist with …
- a completed PhD in structural biology, biochemistry, or chemical biology
- hands-on experience in cryo-EM data collection and processing (single-particle analysis and/or cryo-ET), in vitro reconstitution of multi-protein assemblies and/or familiarity with RNA, DNA or lipid biochemistry
- a publication record with first-author contributions demonstrating this expertise
- a strong interest in ubiquitin biology, innate immunity or proteostasis networks
What We Offer
We offer a 3-year postdoctoral position, with possibility of extension, and a few extras …
- a unique head start: multiple E3 ligase samples are available that offer immediate entry points for high-impact structural and functional studies
- access to cutting-edge cryo-EM/ET, mass spectrometry, imaging facilities, and service platforms at the Vienna BioCenter
- a stimulating, open, and international research environment with strong support for career development; all coming with Vienna, one of the most liveable cities on this planet
How to Apply
The position is available immediately and will remain open until filled. Please send a letter of motivation, CV (including a description of research experience and key contributions), and contact details for two referees to:
Dr. Tim Clausen - tim.clausen[at]imp.ac.at
Additional Information
IMP – https://www.imp.ac.at
Clausen Group – https://www.imp.ac.at/groups/tim-clausen
Ubiquitin Club Vienna - https://www.protein-degradation.org/
Related Publications
Grabarczyk et al (2025) A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles, Cell, 188, 1–17
Grabarczyk et al (2025) Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control, Science, 389, 909-914
Ahel et al (2025) ATP functions as a pathogen-associated molecular pattern to activate the E3 ubiquitin ligase RNF213. Nat Commun, 16,4414-4433
Ehrmann et al (2023) Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379, 1117-1123