Reading the secret language of cells

Glycoproteins and glycolipids which are abundant on cell surfaces can now be visualized one molecule at a time

October 13, 2023

One of the ways cells communicate is by bumping to one another. This seemingly simple event triggers a cascade of molecular interactions, shaping our health, immunity, and even our response to diseases like HIV and Covid-19. Teaming up with collaborators from the University of Oxford, the University of Tübingen, and the University of Copenhagen, scientists at the Max Planck Institute for Solid State Research have developed a new method to visualize the molecules that mediate the secret conversations between cells.

An image of a glycoprotein, showing the glycan bonded to the protein. Imaging the glycoprotein on surface allows us to locate the glycan along the protein chain and determine its molecular structure. Shown here is an unfolded glycoprotein named “RNase B” whose function is to disassemble RNAs into simpler molecules.

Glycans or carbohydrates attached to proteins and lipids are considered the language of cells. The glycan-decorated proteins (or glycoproteins) and glycan-decorated lipids (or glycolipids) are found abundantly on cell surfaces. With many important biological roles, they are essential for the survival of living organism. Yet, despite their importance, figuring out what glycoproteins and glycolipids are present on cell surfaces of bacteria as well as of human cells remains an extremely challenging task for today’s analytical technology. The team of the Max Planck Institute for solid state research has developed a method to visualize them at the single molecule level, allowing their structures to be analyzed one-molecule-at-a-time.

Figuring out glycoprotein and glycolipid structures is very important for the development of new vaccines and medicines, and for an understanding of how cells communicate and how diseases progress. For example, key proteins involved in HIV or SARS-Cov2 infection are densely covered with glycans that enable them to escape neutralization by our immune systems.

Scanning tunneling microscopy for single molecule visualization

An image of a glycolipid, showing the glycan bonded to the lipid. Imaging the glycolipid on surface allows us to determine the molecular structure of glycan bonded to the lipid. Shown here is a glycolipid named “GM3” that are found with unusual abundance on cancer cells.

To address the analytical gap in this problem, the researchers directly image single glycoproteins and glycolipids by scanning tunnelling microscopy (STM) at cryogenic temperatures. To accomplish this, glycoproteins and glycolipids dissolved in solutions are brought to the gas-phase as ions, soft landed at a surface, and imaged by STM at single molecule level. STM allows non-destructive, direct visualization of the molecules, revealing their structures one-molecule-at-a-time. In STM, an image of the nanoscale world is obtained by scanning a sharp metallic tip over a surface and measuring the amount of electric current that flows between the tip and the surface due to electron tunnelling.

The researchers show that STM imaging allows glycoproteins and glycolipids to be analyzed at single molecule level. STM imaging reveals not only the site where the glycan connects to its host molecule, but also the structure of every glycan connected to the host, thus providing structural information that remains inaccessible by the present technology. To show the perspective of the techniques, the team images a wide range of glycan-decorated molecules, such as GM3 and GD3 glycan-decorated lipids, and MUC1 glycan-decorated proteins – all of which are known to be present in cancer cells. The technique thus allows ‘the sugar code’ to be read directly for the first time.

KA

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