Learning how cells get rid of unwanted materials is key to potential new therapies, scientists say

Are you sick and tired of being sick and tired? A UNLV-led research team is investigating whether the reason we sometimes feel sick is because our body’s cells are suffering from the waste that builds up within them.

Gary Kleiger, professor and chair of the department of chemistry and biochemistry at UNLV, along with Brenda Schulman, director of the Munich-based Max Planck Institute for Biochemistry, and their teams are working on ways to help our bodies track and to destroy diseases. causing proteins.

They are the authors of a groundbreaking new study, “Cullin-RING ligases target substrates with geometrically optimized catalytic partners,” published in the journal Molecular cell, this allows us to better understand how enzymes called cullin-RING ligases (or CRLs) help cells get rid of proteins that are no longer needed. The results also point to a potential Achilles heel for proteins that make us sick.

“Cullin-RING ligases (CRLs) are complex nanomachines that are crucial for complex cell disposal and recycling systems,” Schulman said. “CRLs mark defective, toxic, or unnecessary proteins with a small protein called ubiquitin, and mutations or dysfunctions that alter CRLs are often associated with diseases, such as developmental disorders or cancers.”

The research team argues that because CRLs perform key functions in maintaining the well-being of our cells, it is of fundamental importance to define and understand their molecular mechanisms.

“This is incredibly important work. For example, during COVID-19 lockdowns, some may remember trash piling up on sidewalks in at least some cities, causing a health crisis “, explains Kleiger. “The same goes for our cells, and human diseases can arise, at least in part, because our elimination systems are not functioning properly.”

Learning more about how cells use these processes to remove unnecessary or unwanted materials can potentially accelerate drug discovery studies.

“Researchers have already made incredible progress in ‘hijacking’ CRLs to track down and destroy disease-causing proteins. Many believe this is the next big thing in drug discovery,” says Kleiger. “And by discovering more about how CRLs work in our cells, scientists can use this knowledge to better understand human diseases and to aid this new drug discovery platform.”

CRLs work by marking proteins targeted for destruction with a small protein called ubiquitin, and Kleiger’s lab was the first to show that the rate of ubiquitin transfer approaches speeds that rival some of the fastest reactions known in biology. The results of the current work further show us how cells are able to be selective about what they get rid of, and how proteins are not destroyed by accident.

Over the past 20 years, thousands of scientists have spent billions of dollars researching a therapeutic concept to treat human diseases by combining the enzymes that help break down proteins with the proteins that cause the disease.

LCRs are the overwhelming choice for drug discovery to promote the destruction of pathogenic proteins, and LCR-dependent drugs are already in the clinic and could gain FDA approval within the next one to two years. The work of Kleiger, Schulman and their colleagues advances progress toward tangible solutions.

The new study is just the latest from the Kleiger and Schulman labs to show snapshots of CRLs during the process of marking proteins for destruction. Earlier this month, Kleiger, Schulman and their collaborators published a paper in the journal Nature Structural and molecular biology this allowed scientists to visualize for the first time the precise labeling mechanism, catalyzed by CRLs.