A newly published map of protein interactions (link is external), spanning organisms from yeast and amoebae to mice and humans, offers a ten-fold increase on the number of known protein associations. The researchers that have compiled the latest map uncovered tens of thousands of new protein interactions, which account for approximately a quarter of all estimated protein-protein interactions in a cell.
Proteins operate within complexes and networks, interacting to create molecular machines to carry out key intracellular functions, such as building new proteins or transporting proteins around the cell. However, there are tens of thousands of proteins in human cells (link is external) and for the vast majority of them, we still have no understanding of their function.
This is where the new map of protein-protein interactions comes in to play. Using biochemical fractionation and quantitative mass spectrometry the research team were able to isolate thousands of protein complexes from cells and quantify the individual protein components. They then built a network of interactions that can help predict protein function based on its interacting protein partners. For example, a new and unstudied protein is likely to be involved in protein degradation if it interacts with known members of the ubiquitin-proteasome system (link is external). The proteome map was further validated by independent co-fractionation from evolutionary distant species, affinity purification and functional studies.
Protein complexes from nine different species were analysed: baker’s yeast, amoebae, flies, worms, sea urchins, frogs, mice and humans. The new map moves the goalposts forward in terms of protein interaction networks, enabling the prediction of over 1 million protein-protein interactions across all the different species studies.
The map provides insight into how the different protein interactions evolved over time, and demonstrates that tens of thousands of protein associations have remained unchanged since the first ancestral cell appeared one billion years ago. Many of the protein-protein interactions determined in human cells were seen to be identical to those in other species. This reinforces our common evolutionary ancestry and supports the use of many of the animal models to study the molecular basis for a wide variety of diseases and their different presentations.
If a single interaction is lost from the protein network it can result in disease, and the map is already helping scientists to identify proteins that may contribute to complex human disorders. One example of its use is a newly discovered molecular complex, named Commander, which consists of about a dozen individual proteins. The genes that encode some of Commander’s components had previously been found to be mutated in individuals with intellectual disabilities, though how these proteins work is not clear. As Commander is present in all cells, the researchers disrupted its components in Xenopus, revealing abnormalities in the patterning of the brain cells during embryonic development and providing a possible origin for a complex human condition.
Offering tens of thousands of new interactions this new map of proteomic interactions, across species, promises to open many more lines of research into protein function and disease.