UW receives $17 million to speed protein research

Shape is key to understanding how proteins make life work. Each gene in every organism contains information to make a specific and often unique protein.

Researchers now want to catalog the three-dimensional structures of those proteins, and a UW–Madison team led by biochemists John Markley and George Phillips has received a four-year, $17 million grant from the National Institute of General Medical Sciences, part of the National Institutes of Health, to accelerate the process and reduce its cost.

Scientists believe the protein information will produce major biological advances and improve our understanding of health and disease. Defective proteins are responsible for diseases such as Alzheimer’s, cystic fibrosis, “Mad Cow” and sickle cell anemia. The results could also lead to better medications.

But cataloging protein structures is a daunting task. Scientists estimate that there are many tens of thousands of proteins in organisms from bacteria to humans. Determining the structure of a single protein currently may take months or even years at an average cost of $100,000.

“The goal of our work is to design and improve methods for determining the structures of individual proteins and to extend our understanding of how each protein’s structure relates to its function in nature,” says Markley.

Joining Markley and Phillips on the project are Brian Fox, Hazel Holden and Ivan Rayment. All study protein structures at the Department of Biochemistry in the College of Agricultural and Life Sciences.

The researchers anticipate that the grant will create more than 30 new positions at UW–Madison. It also will likely to lead to close collaborations with several local high-tech companies in areas such as robot automation and protein production.

The scientists will use X-ray crystallography and nuclear magnetic resonance spectroscopy to determine the protein structures. “The UW–Madison has been a leader in these areas,” says Markley, who directs the National Magnetic Resonance Facility at Madison. The university’s position was strengthened recently with the hiring of two additional structural biologists as a part of the Madison Initiative.

Collectively, proteins make and regulate all life. Their structure, or shape, is intimately linked to the function of the protein. Knowing the shape of a protein helps scientists understand how it does its job.

When researchers “solve” a structure, they produce an accurate three-dimensional computer image of the location of thousands of atoms in the given protein. Therefore, solving the structure of every protein in nature would take decades and be extremely expensive. However, proteins appear to fall into “families” of related structures. If the detailed structure of one or a few members of each family is known, it is possible to infer the structures of other family members.

Scientists have already solved the structures of more than 14,000 proteins that belong to between 3,000 and 4,000 families. The new NIH initiative hopes to triple the number of families identified in five years while reducing the cost per structure.

“We want to identify members of new protein families, produce those proteins and determine their structures,” says Phillips. “Our team will concentrate on new types of proteins and also develop methods that will allow us to work with proteins previously thought to be too difficult to analyze.”

Other investigators from UW–Madison contributing to the project include plant molecular biologists Mike Sussman and Rick Amasino, RNA biologist Sam Butcher, biology database specialist Eldon Ulrich, informatics specialist Zsolt Zolnai, computer scientist Miron Livny and electrical engineer Franco Cerrina. Additional scientists rounding out the team are from the Medical College of Wisconsin, Washington State University, Argonne National Labs, The Hebrew University of Jerusalem, the Munich Information Center for Protein Sequences in Germany, Tokyo Metropolitan University, and the Institute of Physical and Chemical Research in Japan.

The NIH supports related studies by seven other teams of scientists. The teams focus on proteins from several different species. The Wisconsin-led team will concentrate on proteins from Arabidopsis thaliana, a small plant in the mustard family. Arabidopsis was the first plant to have its genome completely sequenced.

The results of the UW–Madison study will improve understanding of plant biology, says Sussman. He believes the team will uncover information of importance to agriculture, such as how some plants can survive under harsh environmental conditions, become resistant to pests, or produce compounds of commercial importance, such as medicinal compounds, fibers, and nutrients.

“The Arabidopsis genome codes for 30,000 proteins but we know only a handful of these structures,” Sussman says. “Therefore the possibilities for discovery are sky-high.”

The experience gained from working on plant proteins will be directly applicable to unraveling the biology of other organisms, including humans, according to Ulrich. “Many Arabidopsis genes have counterparts in the genomes of mammals and of other species,” he says. “At least 36 of those genes have been implicated in a variety of human diseases.”