Scientists Uncover Protein Folding Quality Control Regulator, Bringing Hope for New Drug Development

A paper published in the latest issue of the Proceedings of the National Academy of Sciences of the United States on August 13 shows that researchers at the University of Massachusetts Amherst in the United States have made a major breakthrough in the study of human protein folding. They have successfully identified the "quality control" regulator of human protein folding, and this discovery is expected to help develop new drugs targeting misfolded sites.

When there are problems with human protein folding, it can trigger many serious diseases such as emphysema, cystic fibrosis, Alzheimer's disease, etc. Although the human body has a quality control system that can recognize misfolded proteins, the operating mechanism of this system has been unknown until now.

Proteins are the basic building blocks of life. Approximately 7,000 kinds of proteins involved in the cellular secretion pathway need to be precisely folded to perform key functions. This process starts in the endoplasmic reticulum and involves the enzyme UGGT and the chaperone protein Sep15. Previous studies have shown that UGGT judges whether the protein folding is correct by reading the carbohydrate tags (N-glycans) in the protein.

In the human body, there is a special "selenoprotein club". Only 25 of approximately 20,000 proteins are selenoproteins, and Sep15 is one of them. And it always binds to UGGT for unknown reasons. Using the "AlphaFold 2" AI model, the researchers predicted that Sep15 would form a helical structure similar to a catcher's glove, which can tightly bind to a specific site of the UGGT enzyme, and this site is precisely the key position where UGGT reads the N-glycan "code" to determine whether the protein folding is correct.

To verify the prediction, the researchers conducted experiments and interfered with the binding of UGGT and Sep15 through recombinant DNA technology. The results showed that the modified UGGT could not function effectively. Regarding the specific role of Sep15, the researchers proposed two hypotheses: one is to give misfolded proteins the opportunity to correct their shape, and the other is to label them for destruction. Although the specific mechanism awaits further exploration, this study paves the way for new drug therapies targeting the Sep15/UGGT interface, which is a new and unexplored field in pharmaceuticals.