Study Of Proteins Offers Insights Into Organization Of Biological Networks

Dana-Farber Cancer Institute investigators report that "hub" proteins – highly connected proteins that bind to many other proteins in the cell – can be divided into two general groups: "party" hubs, which interact with most of their partner proteins all at once, and "date" hubs, which bind to their partners at different times or locations. The study will be published online by Nature as an Advanced Online Publication on June 9 and later in the print edition.

"Our discovery answers a key question about how yeast cells organize their genetic and protein activity," says Dana-Farber's Marc Vidal, Ph.D, who led the study with colleague Jing-Dong Han, Ph.D. "This might turn out to be critical knowledge for the development of drugs for cancer and other diseases."

The new study is based on a map of the interactions among proteins – the so-called "interactome" – in yeast cells. Resembling a ball exploding into thousands of colored particles, the map gives a composite view of interactions that can take place among the proteins, but it doesn't indicate how frequently protein partners interact, nor which partners are in action at the same time. "We need a way of analyzing proteins' activity as a dynamic process," Vidal says.

Vidal and his colleagues focused on hub proteins, the social butterflies of the molecular world, which have large numbers of partner proteins. Researchers theorize that abnormal versions of hub proteins are especially influential in the development of cancer and other genetic diseases. Physicist Albert-Laszlo Barabasi of the University of Notre Dame, for example, has used computer modeling to discover that removing hubs from a network is more likely to result in the network's disintegration than the removal of non-hubs. And biologists have shown that without the genes for hub proteins, yeast cells are three times more likely to die than if they lack the genes for non-hub proteins.

In their Nature study, Vidal and his colleagues sought to understand why hub proteins play such a seemingly central role in cell life. By entering into a computer all that is known about the interactions among yeast-cell proteins, the investigators were able to make a digital simulation of the protein network. They selectively removed hub and non-hub proteins and measured how this affected the overall number of connections between proteins. They found that while eliminating non-hubs had very little effect on the amount of connections, eliminating hubs caused connection length to increase. "The extent of disruption caused by removal of hubs is clearly greater than that caused by removal of non-hubs," Vidal remarks. "It's as though one closed a main road in a city, forcing traffic to follow a lengthy detour to reach its destination."

Analyzing data generated by gene-chip technology, investigators found that some hubs are active at the same time as their partners – like bulbs in a flashing sign – while others are active at different times – like bulbs blinking on a Christmas tree. They dubbed the first group "party" hubs and the second group "date" hubs.

When party hubs were taken out of the mix, there was very little effect on the number of protein connections within the cell. When date hubs were removed, however, connection length rose sharply, meaning it take more "hops" to move between nodes.

Researchers concluded that party hubs work primarily within "modules" that perform specific biological functions, whereas date hubs connect modules to one another. The researchers suggest that a similar structure could be found in many other man-made and natural networks.

"To compare it to the World Wide Web, a party hub is similar to a home page, which has links to all the other pages at that site," Vidal observes. "A date hub would be like a 'Related Links' icon that enables you to jump from one home page to another."

Researchers hope to determine whether this pattern holds for other types of cells as well and, ultimately, whether it provides insights into how gene systems go awry in cancer and other diseases.

###The study's other authors include Nicolas Berlin, Tong Hao, Denis Dupuy, Ph.D., Albertha Walhout, and Michael Cusick, all of Dana-Farber, and Debra Goldberg, Gabriel Berriz, Lan Zhang, and Frederick Roth of Harvard Medical School. The work was supported by grants from the National Human Genome Research Institute, the National Institute of General Medical Sciences, and the National Cancer Institute.

Dana-Farber Cancer Institute (http://www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.