A study on the carbohydrate chondroitin sulfate (CS) reveals that it harbors a sulfation code: The carbohydrate encodes functional information sequence-specifically, similar to DNA and proteins. The findings have implications for understanding processes like neuronal development, viral invasion, and spinal cord injury.
CS is found in joints and cartilage and is sold as an over-the-counter arthritis treatment. Many researchers assumed that the role of CS and related glycosaminoglycan polymers was primarily structural and gave them short shrift as a focus of study.
Others suspected that glycosaminoglycans played a functional role as well, and variable sulfation was suggested as a way their bioactivity might be modulated. But a systematic functional understanding of glycosaminoglycan sulfation was hampered by the structural complexity and heterogeneity of these polysaccharides.
Researchers had no way to study CS sulfation without synthesizing CS oligosaccharides having specific sulfation patterns, which is extremely difficult. Associate professor of chemistry Linda C. Hsieh-Wilson of California Institute of Technology and coworkers worked out a way to do this.
They synthesized four CS oligosaccharides with sulfate groups positioned at precise locations along the carbohydrate backbone and studied their ability to bind to endogenous proteins (Nat. Chem. Biol., DOI: 10.1038/nchembio810).
The work shows that specific sulfation patterns act as molecular recognition elements for growth factors and affect neuronal growth. "Only one of the four sulfation patterns has neuritogenic [nerve-growth-stimulating] activity and binds to growth factors in the brain," Hsieh-Wilson says. "It's the 3-D structure of this carbohydrate that's allowing it to bind to specific proteins and modulate activity."
"It is a heroic piece of work," says chemistry professor Carolyn R. Bertozzi of the University of California, Berkeley, reflecting on the synthetic difficulties involved. "This is one of the first studies I am aware of that demonstrates sequence-specific binding of a protein to CS." Previously, such activity had been shown definitively only for the related glycosaminoglycan heparan sulfate. Bertozzi notes that the new study "will elevate people's appreciation of CS as a polymer that encodes information rather than simply a structural component of tissues."
Chemistry professor Samuel J. Danishefsky of Memorial Sloan-Kettering Cancer Center and Columbia University says the work "establishes the possibility that sulfation provides an important part of the grammar by which neuronal cell surface communication is transacted. While the concept will still require further validation, it's a most exciting idea." He notes that the achievement was made possible by the Caltech group's extraordinary synthetic skill.
Hsieh-Wilson believes the approach will aid the study of mechanisms by which CS and other glycosaminoglycans regulate neuronal growth and brain development. The findings also have clinical implications, she says, "such as the potential to use specific sulfated compounds to control the activities of growth factors for cancer or neuroregeneration or to develop antiviral or anti-inflammatory agents."