Researchers at the University of Toronto and the Hospital for Sick Children have recorded the most comprehensive and reliable map of protein interactions in a living organism to date, bringing science one step closer to deciphering and correcting disease-causing genetic instructions in humans and animals.
The findings, which will be released in the March 30 issue of Nature, reveal how researchers used sophisticated proteomic techniques to identify close to 4,000 proteins and 550 protein complexes involved in 7,123 protein-protein interactions in yeast cells, about half of which are novel. Many of the same complexes and protein interactions that go awry in human disease are also found in yeast. While living yeast cells have only 6,000 genes compared to a human’s 25,000, the structures of their encoded proteins and interactions among the proteins are virtually identical to ours.
“Human proteins involved in disease and protein interactions gone awry found in humans are often found in yeast,” says Professor Andrew Emili of U of T’s Banting and Best Department of Medical Research, the study’s co-author. “By studying and mapping out sets of protein interactions within this basic organism, we are providing the foundation to move into a more complex organism such as a mouse and then a human.”
To map the protein complexes within the cell, researchers combined purification techniques with analysis using mass spectrometry, a technique that breaks down and identifies chemical substances within molecules. Using the combined approach of purification and mass spectrometry, the researchers were able to ensure accuracy and reveal more than 250 complexes that have not yet been reported in previous public databases. The researchers have posted their current findings on a publicly available comprehensive database (http://tap.med.utoronto.ca) and hope the findings will spur further advances within the scientific community. “This database will be linked with other sites, so that results can be compared and contrasted,” says co-author Professor Jack Greenblatt, also of U of T’s Banting and Best Department of Medical Research. “The methods we used to identify protein interactions and protein complexes in yeast appear to be the best currently available, and so are likely to be used soon to identify protein interactions involved in human disease.”
“Large-scale, systematic and holistic projects like the one undertaken by Drs. Emili and Greenblatt and their co-authors are at the core of the unique benefits of genomics and proteomics research strategies,” says Christian Burks, president and CEO of the Ontario Genomics Institute, which provided funding support. “The resource they have created, containing the results of this and similar future studies, will allow researchers to much more rapidly understand the signalling, regulatory and catalytic pathways in the cell, and to apply these insights to human medicine as well as to agriculture.”
The next step, according to Emili, is to analyse these new complexes to determine their roles in living cell functions. “Now that we have the pieces of the puzzle, we have to put them together to get the overall picture,” Emili says. “It is painstaking work, but it brings us closer to answer science’s most fundamental question: how does life operate?”
The research was funded by the Canadian Institutes of Health Research, Genome Canada through the Ontario Genomics Institute, and a grant from the Hospital for Sick Children.
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