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Scripps, Burnham Institutes Receive NIH Roadmap Grants To Study Membrane Proteins, Proteolysis

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The Scripps Research Institute and the Burnham Institute have each received multimillion dollar grants from the US National Institutes of Health to study proteins.

Researchers at Scripps will be studying membrane proteins over the next five years using their $14.5 million grant, while researchers at the Burnham Institute will be studying proteolytic pathways using their $18.2 million NIH grant.

“It is an extremely important grant,” said Scripps professor Kurt Wuthrich, an investigator on the grant and the recipient of the 2002 Nobel Prize in Chemistry. “It fills a very important gap in the whole proteomics field.”

The NIH grants were awarded to the two La Jolla, Calif.-based institutions as part of the $2.1 billion NIH Roadmap for Medical Research, which seeks to speed the movement of research discoveries from the bench to the bedside. The NIH roadmap includes three proteomics-focused trans-NIH initiatives: the National Technology Centers for Network and Pathways, the Standards for Proteomics and Metabolimics/Assessment of Critical Reagents for Proteomics, and Protein Production Facilities (see ProteoMonitor 10/3/03).

Scripps researchers seek to study membrane proteins in part because they have enormous medical potential, said Scripps professor Raymond Stevens, the principal investigator on the NIH grant. A large proportion of drugs on the market target membrane proteins, which make up more than a third of all proteins in the body.

Stevens has spent most of the last decade developing high-throughput methods for solving the structures of proteins.

“Everybody feels that structural biology needs better tools for producing certain types of proteins, particularly for membrane proteins,” said Stevens.

A central problem that Scripps researchers aim to address is large-quantity membrane protein production. Membrane proteins are difficult to study because they are unstable once they are produced. In order to study their structure using X-ray crystallography or NMR, typically several milligrams of the proteins are needed. Such relatively large quantities are hard to produce. In addition, even after the proteins have been produced, they are hard to purify because they are only stable in the presence of the cell membrane, or lipids that act like a membrane.

“The preparation of membrane proteins in the quantities and qualities needed to do structural studies is an unsolved problem,” said Wuthrich. “And we hope to solve it.”

Despite the difficulties in working with membrane proteins, Scripps assistant professor Geoffrey Chang solved the X-ray crystallography structure of a membrane transporter protein for the first time in 2001. The protein Chang described plays a role in cancer cells resisting chemotherapy and bacterial cells resisting antibiotics. The structure was featured on the cover of the Sept. 7, 2001, issue of Science.

“Ten years ago, people thought it would be very difficult to solve kinase structures. Now they are being solved left and right,” said Stevens. “The same could happen with membrane proteins — we just need that technological breakthrough to unleash it.”

Aside from Stevens, Wuthrich and Chang, other Scripps researchers who will be receiving funding from the NIH grant to study membrane proteins include MG Finn, Peter Kuhn, Mark Yeager, Qinghai Zhang and Scott Lesley.

At the Burnham Institute, NIH funds will be used to develop a new proteomics research center called the Center on Proteolytic Pathways.

According to Burnham researchers, proteolytic pathways are significant because proteolysis, or the break-down of proteins, regulates four fundamental aspects of cell behavior: apoptosis, division, differentiation and motility. Understanding the proteolytic process is critical to designing new therapies based on promoting or inhibiting cellular behaviors, the researchers stated.

The new Center on Proteolytic Pathways will concentrate on using activity-based proteomics to profile protease function. This approach, developed by Mathew Boygo from Stanford University, is an innovation that differs from other proteomics strategies because the activity-based approach reports on protease actions, as opposed to just abundance.

Ultimately, the center will consolidate all known and emerging knowledge about how proteins behave into a product called the Protease Pathway Interrogation Platform.

“The center should ultimately help define the physiologic and pathophysiologic role of every human protease,” said Burnham’s Jeffrey Smith, the director of a team of researchers who will be developing the new center.

In addition to creating the PPIP, the center will develop a platform for screening small molecular libraries against all proteases encoded by the genome.

Based on this type of screening, Smith published results earlier this year in the journal Cancer Research that showed that the drug Orlistat, which was approved by the FDA for the treatment of obesity, also acts to inhibit prostate cancer.

“These tools will give us a completely new way of looking at complex biological processes, allowing us to actually watch them in action,” said NIH Director Elias Zerhouni, who announced the NIH’s roadmap last year. “As the centers refine the technologies, these valuable resources will be made available to hundreds of investigators across the country who are working in every disease area.”

Aside from Smith and Boygo, other researchers who will be developing the Center on Proteolytic Pathways include Guy Salvesen, Alex Strongin, Adam Godzik and Andrei Osterman of the Burnham Institute; Bonnie Sloane of Wayne State University; and Lisa Coussens of the University of California at San Francisco.

— TSL

 

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