RESEARCH: CANCER
FOLDING PROJECT #18019 PROFILE

Scientists are using computer simulations to study how a protein called NEDD8 activates another protein called VHL. VHL is part of a system that tags other proteins for destruction in cells. This research could help us understand how diseases develop and create new drugs.

In this system we are simulating an E3 ligase (specifically, culling-ring-VHL) in presence of another protein called NEDD8.

Culling ring is normally in inactive form, but NEDD8 can activate it.

Using these simulations we are trying to understand how protein-protein interactions help induce conformational changes that enable activation of cullin ring.

Understanding this process help us better understand how cullin-ring based E3 ligases transfer ubiquitin to proteins which results in their subsequent degradation by the proteasome system. This is a project run by Roivant Sciences (formerly Silicon Therapeutics) as was officially announced in this press release: https://foldingathome.org/2021/04/20/maximizing-the-impact-of-foldinghome-by-engaging-industry-collaborators/ All data is being made publicly available as soon as it is received at https://console.cloud.google.com/storage/browser/stxfah-bucket.

E3 ligase

Enzyme that attaches ubiquitin to proteins for degradation.

E3 ligases are crucial enzymes involved in marking proteins for destruction within cells. They work by attaching a small protein called ubiquitin to target proteins, essentially acting like a signal flag that tells the cell's recycling machinery (the proteasome) to break down the tagged protein. This process is essential for regulating various cellular functions, including cell cycle control, DNA repair, and immune responses.

cullin ring

A protein complex that forms the core of an E3 ligase.

Cullin rings are multi-subunit complexes that act as scaffolds for assembling E3 ligases. They provide a platform for interacting with various proteins involved in ubiquitination, including substrate recognition factors and the RING domain protein. The structure of the cullin ring is flexible and can undergo conformational changes upon activation by NEDD8, allowing it to bind to specific substrates and facilitate their ubiquitination.

NEDD8

A small protein that activates cullin rings.

NEDD8 (Neural precursor cell expressed, developmentally down-regulated 8) is a ubiquitin-like protein that plays a key role in regulating protein function. It works by attaching itself to specific target proteins, known as NEDDylation, which can alter their activity, localization, or interactions with other molecules. In the context of E3 ligases, NEDD8 modification of cullin rings is essential for activating these complexes and promoting ubiquitination.

ubiquitin

A small protein that tags proteins for degradation.

Ubiquitin is a highly conserved 76-amino acid protein that plays a central role in cellular processes such as protein degradation, signal transduction, and DNA repair. It functions by attaching to target proteins through an enzymatic cascade involving ubiquitin-activating (E1), conjugating (E2), and ligase (E3) enzymes. The attachment of ubiquitin chains to proteins serves as a signal for their recognition and degradation by the proteasome, a cellular machine responsible for breaking down unwanted or damaged proteins.

proteasome

A cellular complex that degrades proteins.

The proteasome is a large, barrel-shaped protein complex found in eukaryotic cells. It plays a crucial role in degrading unwanted or damaged proteins by breaking them down into smaller peptides. The process of protein degradation by the proteasome is tightly regulated and involves multiple steps, including ubiquitination (the attachment of ubiquitin tags) and translocation of the target protein into the proteolytic chamber of the proteasome. This ensures that only specific proteins are degraded at appropriate times.

Roivant Sciences

A pharmaceutical company focused on developing new drugs.

Roivant Sciences is a biopharmaceutical company that leverages technology and data science to accelerate drug development. The company focuses on acquiring intellectual property rights for promising therapeutic candidates and bringing them through clinical trials to market. Roivant has established several subsidiaries, each specializing in different therapeutic areas, such as oncology, neurology, and infectious diseases.