Special arrangements of sulfate groups on certain molecules encourage branching and outgrowth of neurons.

The long chains of sugars that dot the surfaces of cells have been linked to vital processes—such as cell motility, blood clotting, and nerve regeneration—but their precise structures and functions have remained elusive, in large part because of their chemical complexity.

Now the secret is out: These chains, called glycosaminoglycans, have a structural code analogous to that of DNA and proteins.

HHMI investigator Linda C. Hsieh-Wilson and colleagues at the California Institute of Technology have taken the first steps toward cracking this code by looking at chondroitin sulfate, a carbohydrate found in the brain and joints—and in many over-the-counter arthritis medications. Chondroitin sulfate consists of two alternating sugars (N-acetylgalactosamine and glucuronic acid) that form the chain's “links.” Adding to its complexity are sulfate groups that adorn the chain along its length in a seemingly random fashion.

The conventional view was that the sulfate groups attract water and provide much of the shock-absorbing properties of cartilage. But Hsieh-Wilson wondered if their positions along the sugar backbone could direct the three-dimensional structures of the molecules, thus encoding protein-binding sites and other information.

To test this idea, she developed a method to synthesize four molecules of chondroitin sulfate, each with a different pattern of sulfate groups. Hsieh-Wilson then used microarrays to look at the ability of different neuronal growth factors to bind to the synthetic molecules. She also investigated whether the different forms of chondroitin sulfate would promote neuronal cell growth.

Only one of the four sulfated molecules bound to growth factors and stimulated nerve growth, suggesting that a sequence-specific code on chondroitin sulfate enables protein binding. The work was published in July 2006 in the advance online version of Nature Chemical Biology, and appears in the September 2006 print version of the journal.

“This is the first direct evidence that the sulfation patterns of chondroitin sulfate encode specific information,” says Hsieh-Wilson. “We're at the early stages of learning the grammar of glycosaminoglycans, but these experiments suggest that they have much to teach us.”

Photo: Reprinted with permission from Journal of the American Chemical Society 2004: 126, 7736-7737. Copyright 2004 American Chemical Society.