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Proteins are building blocks in the human body, carrying out essential services in our cells, such as replicating DNA, catalysing biochemical reactions, building bone and muscle tissue, transmitting signals, ferrying material across cells, and much more. Every cell comprises nearly 30 000 different proteins, each with a specific job to do.
To keep this complex machinery running correctly, the body has built-in biochemical systems that can turn proteins on and off as needed.
“A major way proteins are turned off is through a tagging system that marks certain proteins for destruction and a giant recycling system that eliminates the tagged proteins,” explains Brenda Schulman, director of molecular machines and signalling at the Max Planck Institute of Biochemistry.
Proteins targeted for recycling are tagged with a small protein called ubiquitin. This tagging is coordinated by enzymes called E3 ligases.
Many of these E3 ligases are in turn regulated by a ubiquitin-like protein called NEDD8, which can switch the ligases on when they are needed and off when it’s time for them to be disassembled.
As with any complex system, sometimes things don’t go as planned. “It is essential that only those proteins that are no longer needed be tagged,” says Schulman. “When the tagging system doesn’t work correctly, the result can be cancer, heart disease, or neurodegenerative disorders.”
With the support of the Nedd8Activate project, which was funded by the European Research Council, Schulman is leading an effort to understand how E3 ligases are activated and regulated by NEDD8. “We believe that understanding this relationship could be the key to developing effective therapeutic solutions for treating those diseases caused by their dysfunction,” she adds.
Witnessing the protein tagging process
By devising new tools that blend chemistry and biology, as well as using an innovative imaging method called cryo-EM, the project was able to get an inside look at the tiny machines operating within our cells. “Knowing what these machines look like is the first step to understanding how they work,” notes Schulman.
For the first time ever, researchers saw how certain ligases tag their targeted proteins. “This process is extremely rapid, taking only milliseconds to happen,” remarks Schulman. “But our approach allowed us to witness how these complexes would perform a chemical reaction.”
Researchers also built cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases. Each constructed CRL had a specific part left out, which allowed the team to deduce what those parts are supposed to do.
Using this approach, the project discovered how the CRL system avoids mis-tagging unneeded proteins. “Much like how a factory can reuse materials to swiftly adapt to changing demands, CRLs can quickly assemble new active complexes when needed – a process that prevents the unnecessary build-up of unused components,” explains Schulman.
Opening the door to new therapeutic strategies
By successfully visualising protein tagging, the Nedd8Activate project has opened the door to leveraging this process to develop new therapeutic strategies for treating disease. “Targeted protein degradation, where drugs bridge disease-causing proteins to CRLs, is a very hot and exciting area of drug development,” notes Schulman.
On this front, project researchers can see how a drug-like molecule can induce CRL tagging of a disease-related protein for degradation. Although not a medicine itself, this finding represents an important step towards potentially using CRLs to fight different diseases.
“We hope discoveries like this, along with all the knowledge and tools developed during the Nedd8Activate project, will serve as catalysts for innovation within the biotech industry, inspiring researchers and entrepreneurs to explore new avenues for drug development that address unmet medical needs,” concludes Schulman. “If this happens, I am confident that we can enhance treatment options for an array of diseases while also fostering growth in the biotechnology sector.”