Â鶹ÒùÔº

One of the great biological mysteries of the human body is how hundreds of complex, origami-like proteins, many of which are crucial for normal body function, come to assume their final, correct shape.

Detailing exactly how this process occurs, which involves a special code, written with carbohydrates on the proteins themselves and known as the "glyco-code," was the life's work of Daniel Hebert, professor of biochemistry and molecular biology at the University of Massachusetts Amherst. Before his untimely death this past winter, Hebert, along with his UMass Amherst co-authors, composed a magnum opus of everything that we now know about the glyco-code.

The work was recently in Nature Reviews Molecular Cell Biology.

Scientists once thought that the single code governing life was DNA, and that everything was governed by how DNA's four building blocks—A, C, G and T—combined and recombined. But in recent decades, it has become clear that there are other codes at work, especially in building the intricately folded, secreted proteins that are created in the cell's protein factory, the endoplasmic reticulum (ER), a membrane-enclosed compartment where the folding begins.

Approximately 7,000 different proteins—one third of all the proteins encoded in the human genome—mature in the ER. The secreted proteins—collectively known as the "secretome"—are responsible for everything from our body's enzymes to its immune and digestive systems and must be formed correctly for the human body to function normally.

Special molecules called "chaperones," help fold proteins into their final functional shape. They also help to identify proteins that haven't folded quite correctly, giving them a second chance to refold properly, or, if they're hopelessly misfolded, targeting them for destruction before they cause damage.

However, the chaperone system itself, which comprises a part of the cell's quality control department, sometimes fails, and when it does, the results can be catastrophic for our health. There are hundreds of diseases—ranging from emphysema and cystic fibrosis to Alzheimer's disease—that can result from errors in cellular protein production.

So how do the chaperones know how to help fold a protein correctly, or identify a misfolded one?

"The ER is an incredibly cluttered and chaotic environment," says Kevin Guay, Hebert's final graduate student and first author of the new paper. "Dan spent his life detailing how carbohydrate-related chaperones direct the protein folding process and guide proteins to their ultimate locations."

It turns out that the chaperones rely on sugar molecules, called N-glycans, that are attached in specific ways to specific places on the protein.

"It's almost like N-glycans are a postal code using the glyco-code like a home address to deliver a package," says Guay, who, in previous work with Hebert, showed how an enzyme called UGGT used N-glycans to "tag" misfolded proteins so that the chaperones could either try to fix the error or mark the protein for destruction.

The current paper is a comprehensive review that lays out the mechanism responsible for tagging proteins with N-glycans, the role that lectins, or the specific chaperones that can read the glycol-code, play in moving the proteins to their final location, and the way that correctly folded proteins finally leave the cell's ER for their final destination.

"The world of chaperones has been very focused on the proteins themselves as carriers of information," says Guay. "This paper is a paradigm shift in showing, in comprehensive detail, how chaperones bind to N-glycans, how those N-glycans get attached and how the protein with its N-glycan move through the ER."

"Since the placement of the N-glycan now emerges as crucial for the maturation of that specific protein, then continuing Hebert's work into understanding the whole chaperone system as completely as possible is crucial if we want to treat the diseases that can result from misfolded proteins," says Lila Gierasch, distinguished professor in biochemistry and molecular biology and chemistry at UMass Amherst and Hebert's longtime colleague.