World’s Largest Protein Interaction Map Reveals Inner Workings of Cells

A multinational team of scientistssifted through cells of vastly different organisms, from amoebae to worms to mice to humans, to show how proteins fit together to build different tissues and bodies. They say they uncovered tens of thousands of new protein interactions, accounting for about a quarter of all estimated protein contacts in a cell. The collaboration between seven research groups from three countries account for about a quarter of all estimated protein contacts in a cell.

When even a single one of these interactions is lost it can lead to disease and the map is already helping scientists spot individual proteins that could be at the root of complex human disorders, the team points out in an article (“Panorama of ancient metazoan macromolecular complexes”) in Nature. They add that their data will be available through open access databases.

Proteins work in teams by sticking to each other to carry out their jobs. Many proteins come together to form so called molecular machines that play key roles, such a building new proteins or recycling those no longer needed by literally grinding them into reusable parts. But for the vast majority of proteins, and there are tens of thousands of them in human cells, we still don’t know what they do.

This is where the map created by researchers led by Andrew Emili, Ph.D., from the University of Toronto’s Donnelly Centre and Edward Marcotte, Ph.D., from the University of Texas at Austin map comes in. Using a technique developed by the groups, the scientists were able to fish thousands of protein machineries out of cells and count individual proteins they are made of. They then built a network that, similar to social networks, offers clues into protein function based on which other proteins they hang out with. For example, a new and unstudied protein, whose role we don’t yet know, is likely to be involved in fixing damage in a cell if it sticks to cell’s known “handymen” proteins.

The study gathered information on protein machineries from nine species that represent the tree of life: baker’s yeast, amebae, sea anemones, flies, worms, sea urchins, frogs, mice, and humans. The new map expands the number of known protein associations over 10-fold, and gives insights into how they evolved over time.

“For me the highlight of the study is its sheer scale. We have tripled the number of protein interactions for every species. So across all the animals, we can now predict, with high confidence, more than 1 million protein interactions [which is] a fundamentally ‘big step’ moving the goal posts forward in terms of protein interactions networks,” says Dr. Emili, who is also Ontario Research Chair in Biomarkers in Disease Management and a professor in the department of molecular genetics.

The researchers discovered that tens of thousands of protein associations remained unchanged since the first ancestral cell appeared, one billion years ago, preceding all of animal life on Earth.

“Protein assemblies in humans were often identical to those in other species. This not only reinforces what we already know about our common evolutionary ancestry, it also has practical implications, providing the ability to study the genetic basis for a wide variety of diseases and how they present in different species,” says Dr. Marcotte, who notes that the map is already proving useful in pinpointing possible causes of human disease.

One example is a newly discovered molecular machine, dubbed Commander, which consists of about a dozen individual proteins. Genes that encode some of Commander’s components had previously been found to be mutated in people with intellectual disabilities but it was not clear how these proteins worked.

Because Commander is present in all animal cells, the scientists went on to disrupt its components in tadpoles, revealing abnormalities in the way brain cells are positioned during embryo development and providing a possible origin for a complex human condition.

“With tens of thousands of other new protein interactions, our map promises to open many more lines of research into links between proteins and disease, which we are keen to explore in depth over the coming years,” says Dr. Emili.