Researchers have produced a new largest-scale map of human protein interactions that will better enable scientists to trace how genetic changes lead to diseases ranging from cancer to Huntington’s disease. The expanded map, published in the journal Cell,1 is about 30% larger than the combination of all small-scale studies published in scientific literature and suggests that scientists may have been too narrowly focused in tracking the mechanisms responsible for disease.
“The search for genetic connections to disease has been compared to an individual looking for his car keys beneath a streetlight at night,” said Thomas Rolland, PhD, a researcher at Dana-Farber Cancer Institute in Boston, and a co–lead author of the study. “When a police officer asks why he’s looking there, he explains that that’s where the light is. By analogy, the new map casts a wider beam over the area to be searched, where the car keys would lie.”
New Protein-Protein Map
In the study, scientists first searched the scientific literature to identify all the protein pairs that have been tested so far. Of that group, they found 11,000 high-quality interactions, representing less than 10% of all the protein-protein interactions thought to be in the human interactome.
The studies made it appear that less than half of human proteins are densely interconnected while the rest did not participate in any interaction, the researchers found. The pattern suggested to the researchers one of two possibilities: either those proteins interact only rarely with other proteins, or, because previous studies have focused on proteins known to be involved in disease, interactions involving other, less notorious proteins have been overlooked.
To determine which conclusion was correct, the researchers generated a new map by systematically looking for interactions among 13,000 proteins, covering almost half the space to be searched. Unlike smaller-scale studies, which were built around known disease proteins, the new study tested proteins “across the board,” regardless of whether they had previously been implicated in disease.
The result was a high-quality map of almost 14,000 interactions among 4,300 distinct proteins. It is the largest experimentally determined binary protein-protein interaction map yet produced, more than doubling the number of high-quality interactions identified in the past 2 decades by small-scale studies.
Based on the new map, the researchers found that instead of well-known proteins being densely interconnected, their interactions were evenly distributed across the proteome, suggesting that the human interactome is broader than previously thought.
“The map will be especially useful in cancer research,” said Dr. Rolland. “It revealed numerous connections between known and suspected cancer proteins, broadening the landscape for understanding the mechanics behind the disease. Combining our map with the results of small-scale studies, we now know of about 30,000 interacting pairs of proteins in human cells.” ■
Disclosure: For full disclosures of the study authors, visit www.cell.com.
1. Rolland T, et al: Cell. November 20, 2014 (early release online).