NANOLIFE@WORK

Real-Time Studies of Biological NanoMachines in Action by NMR

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Proteins assume a complex 3D structure after manufacture in order to achieve their final functionality. Advanced spectroscopic methods shed light on cellular quality control mechanisms with atomic resolution.

Descrizione progetto (Article)

Genes code for proteins, the ubiquitous molecules responsible for nearly everything a cell does and for higher-order functions of an organism in turn. Misfolding and aggregation are common but, left unattended, can provoke ageing, disease and cell death. To prevent this, nature has evolved enzymatic machinery called molecular chaperones.

The molecular chaperones aid in proper folding and play a role in proteolytic degradation of incorrectly folded proteins in an adenosine triphosphate (ATP)-dependent way. ATP is the energy currency of the cell and the molecular machines require a supply of it to do their work. EU-funded scientists used state-of-the-art nuclear magnetic resonance (NMR) spectroscopy to study chaperone-assisted protein (re)folding for the project 'Real-time studies of biological nanomachines in action by NMR' (NANOLIFE@WORK).

Studies aided in understanding the mechanisms of the ATP-induced conformational cycle (repetitive changes in the conformation of the molecular chaperones between various structures). Researchers also provided insight into a passive mechanism of substrate protection by the chaperone and of chaperone-assisted protein folding.

Protein aggregation in the brain is a hallmark of many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases and cystic fibrosis. Understanding how molecular chaperones do their work could point to new therapies for aggregation-related diseases.

NANOLIFE@WORK put important pieces into the puzzle of how molecular chaperones do their jobs and application of results to the health field could have major socioeconomic impact. Further, atomic resolution of molecular machines in motion will have broad-sweeping relevance for advancing structural molecular biology.