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Chemists make molecular scalpels to clear unwanted proteins from cell surfaces



Chemists make molecular scalpels to clear unwanted proteins from cell surfaces

EGFR, a protein important for promoting cancer growth, shown here in purple, adorns the cell surface (left). After treatment with EGFR-targeted LYTAC, all EGFR protein is transferred to lysosomes, the cell degradation compartments (right). Credit: Stephen Banick

When scientists find a potentially dangerous protein in a cell, they can imagine shrinking to become tiny surgeons, cutting out only the problem molecule and leaving the healthy parts of the cell intact. While skilled hands and sharp instruments could never cut a single protein off the cell surface, a new molecular tool could facilitate cell surgery, according to a study published in nature on July 29.


Stanford chemists have developed a new class of molecules that transfer unwanted proteins from the cell̵

7;s surface or environment to the lysosome, the cell compartment dedicated to protein breakdown. These molecules, called chimeric-targeted lysosomes, or LYTACs, work by selectively labeling a protein with a label that seals its fate for disposing of cell debris. This selective degradation can help researchers study and treat diseases such as cancer and Alzheimer’s caused by surface proteins.

“It’s like a molecular scalpel,” said lead author Stephen Banick, a PhD student in Carolyn Bertozzi’s lab, Professors Ann T. and Robert M. Bass at the School of Humanities and Sciences. “This tool allows you to accelerate the natural breakdown of a single protein among all the different proteins that are on or outside the cell.”

Proteins are vital for many biological processes, such as metabolism and intercellular communication, but some of them can also help diseases such as cancer and avoid immune regulation. Traditional methods of preventing these bad participants include the use of drugs that block the active site of the protein, where other cellular components can bind while the protein is working on them, usually through the movement of atoms. But this blocking strategy is imperfect; sometimes the connecting pocket is too shallow and the inhibitor pops up too quickly. In other cases, the activity of a protein stems from its physical properties, such as its hardness, and not from any active site, so that blocking a small portion of the entire protein is insufficient. In these cases, draining the protein cell is the only option.

Protein degradation as a therapeutic strategy has been particularly popular since the development of PROTAC, or chimeric-targeted proteolysis, 20 years ago. PROTACs that search for and label intracellular proteins for degradation have been successful in research laboratories and early clinical trials, but rely on a degradation pathway that is inaccessible to approximately 40 percent of all proteins that sit on or outside the cell membrane. , Bertozi and Banik did not accept that some proteins – and diseases – would be unavailable.

“My lab has always been interested in what’s going on on the cell surface, which contains all these proteins that are important for immune modulation,” said Bertozi, who is also co-director of the Baker family at Stanford CHEM-N. “We have identified many surface and secreted proteins that we believe play pathogenic roles in cancer, and LYTAC can help us better understand them and study them as medicinal targets.”

The key to the operation of the tool is its bifunctional design. One side of this molecule can be customized to bind to any protein of interest. On the other side is a short amino acid sequence or peptide sprinkled with sugar called mannose-6-phosphate.

This sugar serves as an accounting label for the cell. When a cell builds proteins that belong to the lysosome, it sticks to these sugars to ensure that they reach their destination. “Mannose-6-phosphate acts as a zip code,” Banick said. “These sugars tell the cell, ‘I’m taking this protein into the lysosome.’ Please send me there. “” There are receptors on the surface of the cells that interact with this sugar coating, and when they catch a LYTAC molecule and pull into the cell, the labeled proteins are dragged along with it.

By attaching this label to proteins, LYTACs hijack a shuttle’s natural cellular mechanism designed to escort newly synthesized lysosomal proteins to their new home. But while lysosomal proteins are strong enough to survive the breakdown enzymes they encounter in the lysosome, most proteins are not, so those labeled with the LYTAC method are usually destroyed.

Researchers at Stanford have shown that in cells they can target and break down proteins important for Alzheimer’s disease and cancer. According to them, the protein binding end of LYTAC can be anything that binds to a protein, such as an antibody or an existing drug, so that many other proteins and diseases can be attacked in the future.

“With protein degradation strategies, you can not only expand what is a drug, but also improve the therapies that are already there,” Bertozzi said. “Every cell has lysosomes. Every cell already has a way to break down proteins. No matter what your goal is, if you can get LYTAC there, you can break it down.”


Cellular protein shredders to fight cancer


More info:
Steven M. Banik et al. Lysosomally directed chimeras for degradation of extracellular proteins, nature (2020). DOI: 10.1038 / s41586-020-2545-9

Provided by Stanford University

Quote: Chemists make molecular scalpels to clear unwanted proteins from cell surfaces (2020, July 30) extracted on July 31, 2020 from https://phys.org/news/2020-07-chemists-craft-molecular-scalpels -unwanted.html

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