Science and Technology Daily, Beijing, December 12 (Reporter Zhang Mengran) People usually think that diseases are caused by foreign bodies (bacteria or viruses) invading the human body, but the hundreds of diseases that affect humans are actually caused by the wrong production of cellular proteins. A team led by the University of Massachusetts Amherst in the United States recently used cutting-edge technology to crack the carbohydrate-based code that controls the normal shape of certain proteins that keep the body healthy. The study was published in the latest issue of the journal Molecular Cell.
Scientists once thought that the only code that controlled life was DNA, but in recent decades, it has been recognized that there are other codes at work, particularly in the construction of intricately folded secreted proteins that are produced in the endoplasmic reticulum, the protein factory of human cells, (where protein folding begins). About 7000,1 different proteins (3/<> of all proteins in the body) are manufactured in the endoplasmic reticulum. Secreted proteins are responsible for everything from the body's enzymes to the immune and digestive systems and must be folded properly for the body to function properly.
A special molecule, called a chaperone, helps to fold proteins into their final shape, while also recognizing misfolds and "fixing" them before they cause damage.
The discovery of the "chaperone system" was due to glycoproteomics and mass spectrometry, but the researchers hope it will also answer a question that has been unanswered for 25 years: How does the chaperone know which of the 7000,<> different protein folds correctly?
The answer from this study involves an "endoplasmic reticulum gatekeeper" enzyme called UGGT, and a series of carbohydrate tags called N-glycans, which are linked to specific sites in the protein's amino acid sequence.
The researchers modified the "chaperone" network using CRISPR-edited cells while developing innovative glycoproteomics techniques. They found that the UGGT enzyme "labels" misfolded proteins by placing sugars in specific locations. It's a code that the "companion system" reads and then pinpoints exactly where the problem occurred during folding and how to fix it.
This result opens the door to the eventual treatment of hundreds of diseases caused by misfolded proteins.
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Protein folding is a fascinating subject. While performing a function, proteins fold into specific three-dimensional structures in a short period of time. The analysis and prediction of protein structure can help people understand the mechanism of life activities at the molecular level. The chaperone system has been found to guide proteins to fold into their final shape, as well as to identify and repair faulty folds. In this paper, we found that the UGGT enzyme "labels" misfolded proteins by placing sugars in specific locations, and the chaperone system can read this code. Many diseases are caused precisely by the wrong folding, and understanding how the companion system recognizes errors opens the way for humans to solve similar problems.