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Proteoglycans—molecules consisting of a core protein with multiple sugar chains—are so complex that researchers usually study the protein and sugar components separately, which makes it difficult to understand their overall structure and function. Mia L. Huang and coworkers at Scripps Research in California now report a platform for chemically editing proteoglycans. They have already used the platform to study a proteoglycan involved in the spread of cancer cells (Nat. Chem. Biol. 2022, DOI: 10.1038/s41589-022-01023-5).
The platform lets them precisely control the location and composition of the sugar chains—known as glycosaminoglycans, or GAGs—on proteoglycans. GAGs are long sugars with repeating disaccharide units made of a glucuronic acid and an amino sugar. The disaccharide composition and the glycosidic linkages dictate how the GAGs are classified, the most common being heparan sulfates and chondroitin sulfates.
The researchers’ method involves engineering both protein and GAG components. They used unnatural amino acids with alkyne handles to define the attachment points for the sugar chains on the protein cores. They used azide-linked monosaccharides in order to hijack the biological machinery to make GAGs. The resulting GAGs added to the protein core via a click-chemistry reaction between the alkynes and azides.
For example, the team used the platform to make synthetic versions of various syndecans, a widely studied family of proteoglycans. “We didn’t want to veer too far away from what nature was trying to tell us,” Huang says. “Our initial goal was to be able to ask questions like, ‘Why does nature make these molecules in the way that it does?’”
The researchers used the platform to study the roles of each component of a proteoglycan in the spread of cancer cells. They found that the core protein alone was not sufficient to promote cell spreading—the GAGs were also needed. They also found that the proteoglycan needed to be anchored to the cell membrane rather than in a soluble form outside the cell.
“This method brings us an important step closer to recapitulating the natural system. The ability to mimic full-size proteoglycans and precisely engineer their structures is impressive,” says Linda Hsieh-Wilson, an expert on glycobiology at the California Institute of Technology. “Such tools will enable systematic investigations into different proteoglycan architectures.” In addition, she says, “the work presents another important technology for remodeling glycans on cell surfaces.”
The researchers focused on the portion of proteoglycans on the surface of cells; they didn’t include the portions that are embedded in the cell membrane or inside the cell. The inability to look at those portions of the proteoglycans is a limitation of the method; Huang and her team are working on ways to overcome that limitation.
Huang plans to use the platform to study neurexin, which is involved in the formation of synapses and has only recently been shown to be a proteoglycan. “To me, that discovery was just like, shoot, we don’t know everything yet about all possible proteoglycans in the cell,” she says. She intends to combine her new platform with other methods that identify molecules that are interacting with one another to figure out how neurexin’s interactions change as a function of glycosylation patterns.
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