NanoLife@Work · Real-Time Studies of Biological NanoMachines in Action by NMR

Protein Quality Control is an essential and evolutionary-conserved process that is present in all kingdoms of life. In cells, both newly synthesized and pre-existing proteins are constantly prone to misfolding and aggregation. The accumulation of damaged proteins can perturb cellular homeostasis and provoke aging, pathological states and cell death. Accordingly, cells have developed an enzymatic machinery – molecular chaperones – that rescues misfolded proteins by catalyzing their conversion back to the native state in an ATP-dependent manner.In this project, the candidate will use state-of-the-art expertise in NMR spectroscopy to address the fundamental questions of chaperone-assisted protein (re)folding. The combination of cutting-edge techniques in methyl-specific isotope-labeling and fast, relaxation-optimized NMR methods will allow real-time characterization of the molecular events in chaperone activity on an atomic scale. The candidate will exploit the unique potential of this approach to dissect the chaperone oligomerization pathway, ATP-dependent conformation cycle, and chaperone-assisted protein (re)folding.Understanding the mechanism of chaperone action could help in the design of new therapeutic agents for aggregation-related diseases such as Alzheimer’s disease or cystic fibrosis. Furthermore, the development and use of atomic resolution NMR methods for monitoring active ~1 MDa molecular machines will have a huge impact in structural molecular biology.Finally, the candidate will receive first-class training and career development at a major European structural biology centre. The trans-national move to the host institute will help candidate to build international collaborations and acquire new skills and experience. This diversification and enhancement of scientific and professional competences will enable the candidate to reach a position of professional maturity and independence.