RESEARCH: CANCER
FOLDING PROJECT #18725 PROFILE

This project studies how a protein called TNF-alpha works in cancer. It can help cancer grow or kill it! Researchers are using computer simulations to understand how TNF-alpha changes shape when it binds to other molecules, and how this affects its ability to fight or fuel cancer.

Note: This TLDR is a simplication and may not be 100% accurate.

Tumor necrosis factor α (TNFα) is a cytokine that belongs to a superfamily of trimeric proteins.

This protein has been shown to be important in regulating autoimmune diseases such as arthritis and Crohn’s disease through interactions with the TNF receptor.

In regard to cancer, TNF is a double-dealer.

On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis.

On the other hand, TNF could be a cancer killer.

In it’s apo state TNFα has shown to be symmetrical, but small ligand inhibitors bind the TNFα disrupt this symmetry by forcing one of the monomers to be below the other two, which disrupts the binding interface to form the TNFα-receptor complex.

In this project, we want to determine the stability of the trimer and get a sense of the free energy landscape.

We also want to determine if the asymmetry found in the inhibited conformation requires the presence of an inhibitor or if the apo trimer can visit inhibited states in the absence of the ligand.

In particular we are interested in learning about the effect the volume of the binding pocket has on forming the asymmetrical TNFα complex.

The initial starting structures are 50 diverse seeds from HREMD simulations started from a crystal structure.

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.

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Tumor necrosis factor

A cytokine involved in regulating immune responses and inflammation.

Tumor necrosis factor (TNF) is a protein that plays a crucial role in the body's immune system. It helps to fight infections and regulate inflammation. However, too much TNF can contribute to autoimmune diseases like arthritis and Crohn's disease. In cancer, TNF can have both positive and negative effects, promoting tumor growth in some cases while also helping to kill cancer cells in others.

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Cytokine

A small protein that is secreted by cells and acts as a signaling molecule.

Cytokines are tiny proteins used by the immune system to communicate with each other. They act like messengers, telling cells what to do in response to infection or injury. Different cytokines have different effects, some promoting inflammation while others suppress it.

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Autoimmune disease

A condition in which the immune system mistakenly attacks the body's own tissues.

Autoimmune diseases occur when the immune system, which normally protects us from infection, starts attacking our own healthy cells and tissues. This can lead to a wide range of symptoms depending on which organs are affected.

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TNF receptor

A protein that binds to TNF and mediates its effects.

The TNF receptor is a molecule on the surface of cells that binds to tumor necrosis factor (TNF). This binding triggers a cascade of events within the cell, leading to various responses such as inflammation or cell death.

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Cancer

Uncontrolled growth and spread of abnormal cells.

Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body. These cells can invade surrounding tissues and spread to other parts of the body through the bloodstream or lymphatic system.

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Angiogenesis

The formation of new blood vessels.

Angiogenesis is the process by which new blood vessels are formed. It's essential for normal growth and development but can also be hijacked by tumors to supply themselves with nutrients and oxygen.

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Inhibitor

A substance that blocks or reduces the activity of another molecule.

Inhibitors are molecules that can block or reduce the activity of other molecules, such as enzymes or receptors. They're widely used in medicine to treat diseases by inhibiting the function of harmful proteins.