Sugar-coated proteins come into view

The entire human genome encodes only about 20 000 proteins—not nearly enough to explain all the complexity of our biology. To expand the range of biomolecular functions, our cells decorate proteins with complex sugars called glycans. The same protein might show up in many different contexts, each time wearing a different glycan disguise and performing a different role.

Compared with protein biochemistry, the understanding of glycans is still in its infancy. A share of last year’s Nobel Prize in Chemistry honored the development of the first chemical tools for fluorescently labeling glycans in vivo. That work dates back only to the late 1990s. And it’s not well suited to looking at single molecular structures.

Now Kelvin Anggara, Klaus Kern (both at the Max Planck Institute for Solid State Research in Stuttgart, Germany), and their colleagues have obtained single-molecule images of glycoproteins and other glycan-decorated biomolecules. They used a method based on scanning tunneling microscopy (STM) that Kern and colleagues developed a decade ago and have used on several classes of biomolecules, including proteins and glycans individually.

Researchers have long used STM to image solid surfaces under vacuum in atomic detail, but adapting the technique to the messy biomolecular environment is harder. To turn the molecules of interest into STM samples, Kern and colleagues disperse them into a fine spray, ionize them, run them through a quadrupole to weed out impurities, and land them on a solid surface. Applying the protocol to glycoproteins is challenging: The molecules themselves are scarcer than either proteins or glycans, and there’s a narrower range of surfaces that can catch the molecules without breaking them up.

Surprisingly, the STM images, such as the one in the figure, easily distinguish the glycan and protein parts of each molecule: The yellow and white are false colors, but the glycan domains shine bright, and the protein portions are relatively dim. To interpret their images, the researchers so far have relied on prior knowledge of the proteins’ amino-acid sequences. But they anticipate that by bringing to bear all the tricks of the STM trade, including chemically specialized tips and imaging of electronic orbitals, they’ll be able to study unknown glycoproteins too. (K. Anggara et al., Science 382, 219, 2023 .)