Researchers at the Institute of Biotechnology have published detailed images of the structural 'telephone' used by human cells to talk to each other in their natural environment for the first time, solving one of science's structural mysteries.
Gap junctions are critical for cell-to-cell communication in our bodies. Made up of intricate 2D lattices that connect the cytoplasm of neighbouring cells, these structures allow the cells to talk to each other directly using signals separated from the outside world. The resulting communication coordinates everything from wound healing to our heartbeat, and while scientists knew they were there, no one had managed to see them in action.
For decades these junctions were studied through a method called protein purification, with individual channels being isolated from their natural environment for analysis. However, this stripped away what makes a gap junction a gap junction - hundreds of channels called connexins forming a lattice with their 'tails' free inside the cytoplasm of cells.
"Before, we were studying a brick and trying to imagine the wall," says Juha Huiskonen, Professor of Structural Biology at the University of Helsinki and Director of the Institute of Biotechnology.
Instead of purifying the channels, the researchers froze human cells with the gap junctions intact. They then finely sliced them with a focused beam of ionsand imaged the slices with cryogenic electron tomography. This technology takes snapshots of molecules and combines them to create a detailed 3D image, giving researchers their first look at the junctions embedded in the cells.
The new images correct earlier theories and give a significantly higher level of detail than ever before.
"The big surprise was the C-terminal domain - a large intracellular region missing from every previous purified structure. It turns out to be the molecular glue holding neighbouring channels together, with lipids and cholesterol filling the gaps between them," Huiskonen explains.
These new images give scientists a framework for asking how these lattices form, how they fall apart and how mutations in connexin molecules can cause disease from cardiac arrhythmias to hereditary deafness to skin disorders. The methodology can also be used to investigate other elusive proteins and structures.
While the techniques in this study were performed at the EMBL Imaging Centre in Heidelberg, from 2027 onwards both instruments will be available in Finland thanks to infrastructure funding from the Research Council of Finland and the University of Helsinki.
The wider Finnish research community can look forward to greater insights into cellular structural biology, opening the door to many more landmark discoveries in health and disease.
