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An integrative approach to uncover the multilevel regulation of 20S proteasome degradation

Project description

Unravelling the regulation of the 20S proteasome degradation pathway

Proteasomes are large multi-subunit enzymes ubiquitously found in eukaryotic cells that break down proteins. The proteasome typically consists of a mixture of 30S, 26S and 20S complexes that share common catalytic sites. Until recently, the ubiquitin-26S proteasome degradation pathway was considered the primary route to protein degradation. However, many substrates, among which are key regulatory proteins, have been identified for the ubiquitin-independent 20S proteasome. The European Research Council-funded 20SComplexity project will characterise three levels of 20S proteasome regulation: intramolecular, intermolecular, and via cellular regulatory networks. Using a combination of high-tech biochemical, analytical, imaging and screening approaches in vivo and in vitro, the team will reveal the tightly regulated 20S proteasome-mediated protein degradation pathway.

Objective

For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route.
To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation:
Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome.
Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function.
Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach.
Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.

Host institution

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution
€ 1 500 000,00
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost
€ 1 500 000,00

Beneficiaries (1)