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Deciphering co-translational protein folding, assembly and quality control pathways, in health and disease

Project description

The importance of correctly folded proteins

The mechanisms ensuring proteins’ correct folding and assembly in the crowded cytoplasm are not well known. The growing number of misfolding diseases underlines the importance of the folding challenge. The ribosome emerges as a hub at the critical intersection of synthesis and folding. It was recently discovered that even the final step of folding, the assembly into complexes, is coordinated with translation. Members of the EU-funded RiboFriend project developed a ribosome profiling approach to capture co-translational events in vivo. However, the mechanisms regulating co-translational assembly pathways remain unclarified. The project will explain co-translational protein folding and degradation mechanisms in health and disease, advancing understanding of conformational diseases and the ageing process and opening new pathways for therapy.

Objective

The majority of cellular proteins do not function alone; rather acting together to achieve concerted functions. Despite the prevalence of protein complexes, little is known of the mechanisms that ensure their correct folding and assembly in the crowded cytoplasm. The importance of the folding challenge is underscored by the growing number of misfolding diseases, often characterized by aggregation of lonely, unassembled protein-subunits.
At the critical intersection of synthesis and folding, the ribosome is emerging as a hub, guiding the polypeptide-chain interactions with targeting factors, modifying enzymes and folding chaperones. We have recently discovered that even the final step of folding, the assembly into complexes, is coordinated with translation. To capture co-translational events, in vivo, we developed a ribosome profiling approach. This approach revealed that emerging polypeptide-chains are constantly engaged by their partner subunits, protecting them from misfolding (Shiber et al., Nature 2018). However the mechanisms regulating co-translational assembly pathways remain largely obscure. In this proposal, we aim to elucidate co-translational protein folding and degradation mechanisms, in health and disease.
We will: (i) Identify and characterize novel co-translational degradation pathways, by targeting ribosomes synthesizing misfolding-prone subunits. (ii) Elucidate the conformational, energetic and kinetic parameters directing folding and assembly, at the atomic level, by molecular dynamics (iii) Develop RiboFriend a single-molecule in vivo approach to elucidate the interplay of chaperones, degradation and assembly factors, during synthesis. Our collective preliminary results strongly support the feasibility of this proposal. The ability to capture co-translational folding and misfolding pathways, in single-molecule resolution can revolutionize our understanding of conformational diseases and the aging process, opening new horizons for therapy.

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(opens in new window) ERC-2021-STG

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Host institution

TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 412 500,00
Address
SENATE BUILDING TECHNION CITY
32000 Haifa
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost

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€ 1 412 500,00

Beneficiaries (1)

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