A significant breakthrough at the University of Massachusetts Amherst has unraveled the mystery of how sugars attached to proteins assist in their proper folding, highlighting new avenues for treating diseases linked to incorrect protein folding. The study showcases a protein (depicted in red) that is glycosylated with glycans (illustrated in blue and green), as credited to UMass Amherst.
Critical Insights into Enzymatic Influence on Protein Structure
Research reveals the pivotal role of a specific enzyme in protein folding.
Diseases are often attributed to external invaders like bacteria or viruses, yet numerous human diseases stem from protein production errors within cells. Researchers at the University of Massachusetts Amherst have harnessed advanced technologies, including glycoproteomics, to decipher the sugar-based code that directs the formation of certain protein classes into complex structures essential for health.
Exploring the Enigma of Serpins
Published in Molecular Cell, this research examines serpins, a protein family linked to various diseases. This pioneering study investigates how carbohydrates attached to serpins ensure their correct formation. Diseases such as emphysema, cystic fibrosis, and Alzheimer’s arise when cellular control over protein folding fails. Understanding the glyco-code responsible for precise folding and quality control opens potential paths for drug therapies targeting numerous diseases.
Delving Into DNA and Protein Formation
Previously, DNA was thought to be the sole code dictating life, based on the combination of its four bases—A, C, G, T. However, it’s now evident that other codes play a role, particularly in the formation of complex folded proteins produced in the endoplasmic reticulum (ER), the cell’s protein factory.
Around 7,000 proteins, one-third of the body’s total, mature in the ER. These secreted proteins, or “secretome,” are crucial for functions ranging from enzyme production to immune and digestive system operation, requiring correct formation for normal body function.
The Role of Chaperones in Shaping Proteins
Chaperones are special molecules that aid in folding proteins into their final shapes. They also identify improperly folded proteins, assisting in their refolding or marking them for destruction to prevent damage. However, failures in this chaperone system can lead to severe health consequences.
Groundbreaking Discoveries in Glycoproteomics
Daniel Hebert, a professor at UMass Amherst, initiated the discovery of the carbohydrate-based chaperone system in the ER during his postdoctoral work in the 1990s. Current tools like glycoproteomics and mass spectrometry have enabled researchers to address longstanding questions in this field.
This research probes the mechanism by which chaperones recognize when 7,000 different proteins are correctly folded.
Advancements in Protein Quality Control Understanding
The key involves an enzyme known as UGGT and carbohydrate tags, N-glycans, linked to the protein’s amino acid sequence.
Kevin Guay, a Ph.D. candidate at UMass Amherst, concentrated on two mammalian proteins, alpha-1 antitrypsin and antithrombin. Utilizing CRISPR-edited cells and modifying the ER chaperone network, the team observed how N-glycans affect protein folding. Innovations in glycoproteomics techniques helped understand the role of glycans on protein surfaces.
They found that UGGT “tags” misfolded proteins with sugars at specific sites, forming a code read by chaperones to correct folding errors.
Implications and Future Research
“This is the first time we’ve observed sugars placed by UGGT on proteins in human cells for quality control,” notes Guay. This research establishes a foundation for exploring how sugar tags direct proteins for further quality control, suggesting UGGT as a potential target for drug therapy research.
“The exciting aspect of this research,” adds Lila Gierasch, a distinguished professor at UMass Amherst and co-author, “is the discovery of glycans as a coding mechanism for protein folding in the ER, and the role of UGGT. This opens new opportunities for understanding and treating diseases resulting from protein misfolding.”
Reference: “ER chaperones use a protein folding and quality control glyco-code” by Kevin P. Guay, Haiping Ke, Nathan P. Canniff, Gracie T. George, Stephen J. Eyles, Malaiyalam Mariappan, Joseph N. Contessa, Anne Gershenson, Lila M. Gierasch and Daniel N. Hebert, 4 December 2023, Molecular Cell.
DOI: 10.1016/j.molcel.2023.11.006
Table of Contents
Frequently Asked Questions (FAQs) about Protein Folding Research
What is the key finding of the UMass Amherst study?
The study discovered how sugars attached to proteins guide their proper folding, providing new insights for potential treatments of diseases caused by protein misfolding.
How does this research contribute to understanding diseases?
By investigating how carbohydrates influence the folding of serpins, a family of proteins, the research offers a pathway to target various diseases, like emphysema, cystic fibrosis, and Alzheimer’s, which are caused by errors in protein folding.
What role do chaperones play in protein folding?
Chaperones are molecules that assist in correctly folding proteins and identifying misfolded proteins. They either aid in refolding these proteins or target them for destruction to prevent damage.
What groundbreaking tools were used in this research?
The study utilized advanced glycoproteomics and mass spectrometry techniques at UMass Amherst’s Institute for Applied Life Sciences to explore protein folding and misfolding.
What does the discovery of UGGT’s role in protein folding signify?
The discovery of the enzyme UGGT’s role in tagging misfolded proteins with sugars highlights a new mechanism for quality control in protein folding, opening avenues for targeted drug therapy research.
More about Protein Folding Research
- UMass Amherst Protein Folding Study
- Glycoproteomics Research
- Diseases Linked to Protein Misfolding
- Chaperone Molecules in Protein Folding
- Advancements in Mass Spectrometry
4 comments
really interesting read, didnt know that sugars played such a big role in protein folding.
UMass Amherst is doing some groundbreaking work! it’s incredible how far technology has come, especially in glycoproteomics.
This could be a game changer for treating diseases like Alzheimer’s, can’t wait to see where this research leads.
Wow, this is huge for science! Its amazing to see how much we’re learning about proteins and diseases.