Protein spy spots skin secret

Scientists have developed a powerful microscopy technique that has allowed them to see proteins in their natural environment and interactions inside cells. 

3D visualisation of interacting cadherin molecules in their native arrangement. Known molecular structures of cadherins (grey and red ribbons) are fit into the electron tomogram (multicolour) of the complex.

Using an advanced microscopy technique called cryo-electron tomography, researchers from the European Molecular Biology Laboratory EMBL have visualised proteins responsible for cell-cell contacts in the skin for the first time.

The researchers from the European Molecular Biology Laboratory published the first 3D image of human skin at molecular resolution to reveal the molecular Velcro-like organisation that interlinks cells.

“This is a real breakthrough in two respects,” said Achilleas Frangakis, group leader at EMBL. “Never before has it been possible to look in three dimensions at a tissue so close to its native state at such a high resolution. We can now see details at the scale of a few millionths of a millimetre. In this way we have gained a new view on the interactions of molecules that underlie cell adhesion in tissues – a mechanism that has been disputed over decades.”

So far, the only information available about a protein’s position and interactions in a cell was based on either light microscopy images at poor resolution or techniques that remove proteins from their natural context. With the new cryo-electron tomography technique however, a cell or tissue is instantly frozen in its natural state and then examined with an electron micro-scope. Electron microscopy normally requires tissue to be treated with chemicals or coated in metal, a procedure that disturbs the natural state of a sample. With cyro-electron tomography, images are taken of the untreated sample from different directions and assembled into an accurate 3D image by a computer.

The researchers applied this technique to observe proteins that are crucial for the integrity of tissues and organs like the skin and the heart, but also play an important role in cell proliferation. These proteins, called cadherins, are anchored in cell membranes and interact with each other to bring cells close together and interlink them tightly.

“We could see the interaction between two cadherins directly, and this revealed where the strength of human skin comes from,” says Ashraf Al-Amoudi, who carried out the work in Frangakis’ lab. “The trick is that each cadherin binds twice: once to a molecule from the juxtaposed cell, and once to its next-door neighbour. The system works a bit like specialised Velcro and establishes very tight contacts between cells.”