Researchers at the Center for Eukaryotic Structural Genomics, based at the University of Wisconsin-Madison, have received a $20 million award to fund Phase II of the Protein Structure Initiative over the next five years. Information from the PSI project, funded by the National Institute of General Medical Sciences, will deepen our understanding of a variety of biological processes.
Proteins are everywhere – nearly everything in a living system is protein-mediated. The PSI studies how the information in a gene is turned into a physical protein that does the work in a cell. The three-dimensional structure of each protein determines its function in an organism. PSI centers explore and define these 3-D structures and expand on this knowledge in a systematic way.
“If we can understand the shape of a protein molecule, we can better understand its function. This understanding may allow us to design new drugs to control diseases, develop blood substitutes and synthetic skin, and better understand diseases such as Alzheimer”s, cystic fibrosis and sickle-cell anemia,” says UW-Madison biochemist John Markley, principal investigator on the project. “Currently, about half the genes that code for proteins can be mapped to a physical structure. The other half are still mysteries,” Markley says. “We”re taking a big view of all the proteins rather than studying them one by one.”
In Phase I of the Protein Structure Initiative, UW-Madison researchers studied Arabidopsis, a small plant whose genome has been completely sequenced. During Phase II, they will analyze proteins from humans, mice, rats, yeasts, zebrafish and thermophilic algae.
“We”re developing a technology platform and methods that can be applied systematically to study these unknown proteins,” says George Phillips, a UW-Madison biochemist and co-principal investigator. “In PSI Phase I we generated the first generation technologies; in Phase II we”re applying those technologies and developing an even more efficient ”protein structure factory.” During the first phase we completed over 60 new structures, and 75 percent of them were unique structures that hadn”t been previously modeled. Over the next five years in Phase II, we expect to complete hundreds more.”
Proteins can be classed into “families,”; or groups of similar proteins. There are at least 10,000 known families of proteins and probably many thousands yet to be identified. “If we can solve the 3-D structure of one structure in a family, then this helps us greatly in mapping similar structures from the same group,” says Brian Fox, who completes the group of co-PIs at UW-Madison. “When the Center solves a unique structure, many researchers from both the public and private sectors can directly benefit from this information, which is made freely available through the Protein Data Bank.” (See sidebar)
Joining Professors Markley, Phillips and Fox are Michael Sussman, Director of the UW-Madison Biotechnology Center, and Brian Volkman of the Medical College of Wisconsin.
The researchers will set up a lab complex on two floors of the 445 Henry Mall facility, as well as other labs on campus. The award will support about 30 positions at the UW-Madison. It will also lead to collaborations with local high-tech companies and researchers, including Promega, Bruker AXS, and stem cell researcher Jamie Thomson.
The award establishes a cooperative agreement with the National Institutes of Health. Researchers at the UW-Madison center will coordinate work with the NIH and 10 other PSI centers across the United States to avoid duplication of efforts.