Scientists at Sanford Burnham Prebys have made a remarkable breakthrough in understanding the assembly process of proteasomes, the crucial machinery responsible for recycling most proteins in our cells. Their findings could pave the way for new treatments targeting cancer and age-related diseases.
Just Unpack the Molecular Dance
In the human body, cells produce proteins in a sort of on-demand fashion. The remarkable cellular structure that orchestrates this recycling is called the proteasome.
Proteasomes orchestrate the degradation of almost 80% of our cells’ proteins, maintaining homeostasis as new protein synthesis complements that which has expired or evolved to be misfolded and potentially toxic. This is important because proteasomes have been implicated in cancer and aging, so understanding how they are built enables the development of better therapeutics.
Dr. Jianhua Zhao and his graduate student Hanxiao Zhang from the lab of a research team have presented new insights on the early as well as late stages of proteasome assembly in Nature Communications. Their discovery reveals new details of the molecular dance that leads to the generation of these critical cellular components.
Protein Recycling Weapon
The proteasome (or 20S proteasome) is composed of four stacked rings and each ring contains seven protein building blocks called subunits. Beta Centry: Made up of two rings (alpha + alpha/beta) surrounding the central hole in which one side is blocked by domain I of beta, backward near the side of the entrance to the distal end foot.
To determine with precision how this barrel-like architecture forms, the researchers turned to gene-editing methods that allow them to introduce tags onto chaperones: helper proteins that bind the alpha and beta subunits, facilitating their association into the resulting seven-piece rings.
Using state-of-the-art cryo-electron microscopy (cryo-EM), the images captured by the scientists revealed how these chaperones interact with their respective subunits as they assemble to form rings and then stack on top of one another to build up the final 20S proteasome barrel. It gave us for the first time a real-time view of that process from beginning to end: images of those early stages were now accessible to investigators as short videos.
Conclusion
The research by Sanford Burnham Prebys’s team is poised to transform our understanding of cellular operations and identify new avenues for precision treatments. In revealing the structural underpinnings of proteasome assembly, the researchers have established a platform for investigating new opportunities to utilize this information in the fight against cancer, age-related diseases, and even host-pathogen interactions. We can look forward to further breakthroughs not only in cellular biology but also in the targeted treatment of many diseases as the scientific community takes these preliminary results and runs with them.
