Anyone who has attempted to fold a fitted sheet knows that it’s not an easy task. If you don’t do it correctly, your laundry can end up in a jumbled, wrinkled pile. This is similar to what can happen with around 7,000 proteins in our bodies, which need to be folded in a precise manner to regulate crucial cellular activities. If these proteins fold improperly, serious health conditions, such as emphysema, cystic fibrosis, and Alzheimer’s disease, may arise. Thankfully, our bodies possess a quality-control mechanism that identifies wrongly folded proteins and either sends them for re-folding or for destruction. However, the exact workings of this quality-control system have not been fully understood. Researchers at the University of Massachusetts Amherst have recently made significant advancements in unraveling how this system operates by discovering the crucial ‘hot spot’ where all the action occurs. This research has been published in the Proceedings of the National Academy of Sciences.
While DNA may serve as the blueprint of life, proteins are what construct our bodies. Although many proteins are relatively straightforward in structure, about 7,000 must be produced in a cell’s secretory pathway and then distributed within the cell or secreted outside to carry out their vital roles.
The process begins in the endoplasmic reticulum, which acts like a cellular factory, correctly assembling thousands of different proteins. Two primary components involved in this process are an enzyme named UGGT and the partner protein Sep15. The senior authors of the study, Daniel Hebert and Lila Gierasch, along with graduate student Kevin Guay from UMass Amherst, previously identified UGGT as a “gatekeeper” that decodes carbohydrate markers known as N-glycans incorporated into proteins to assess whether they’ve folded properly.
According to lead author Rob Williams, a postdoctoral fellow in both Hebert’s and Gierasch’s labs, there’s more to the story. “There’s an exclusive group of proteins called ‘selenoproteins,’ containing selenium, which are quite rare. Among approximately 20,000 proteins in our body, only 25 are selenoproteins, and Sep15 is one of them. Sep15 has always been linked with UGGT, but its role has remained unclear until now.”
The research team utilized an advanced AI tool, AlphaFold2, to predict that Sep15 forms a spiral-like structure resembling a catcher’s mitt, designed to fit perfectly with a corresponding site on the UGGT enzyme. This specific point where Sep15 and UGGT connect is also the area where UGGT interprets the N-glycan code to determine if a protein is correctly folded.
Hebert explains, “Essentially, we’ve pinpointed the hotspot for activity— and Sep15 plays a crucial role.”
To validate their findings, the research team conducted experiments by altering UGGT’s recombinant DNA to disrupt its binding with Sep15. As expected, the modified UGGT was unable to form a complex with Sep15.
So, what role does Sep15 play? Hebert indicates, “We are exploring two possibilities: Sep15 may provide a misfolded protein the opportunity to correct its structure, or it could signal the protein for removal.”
Gierasch emphasizes the importance of the proteins being studied, stating, “The complexity of these proteins allows higher organisms to function, but their intricate structures also make them more susceptible to misfolding, which can lead to severe outcomes if the quality control system fails.”
Despite the extensive basic research still required, this team’s findings pave the way for innovative drug therapies that could target the Sep15/UGGT interface. Hebert notes, “This is a promising area for pharmaceutical development, and Williams’s research is steering us toward future treatments.”
This study received support from the National Institutes of General Medical Sciences and was made possible by the resources at the UMass Amherst Institute for Applied Life Sciences.
