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U of Chicago-led Consortium Wins $22.5M NIGMS Grant to Study Membrane Proteins

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By Adam Bonislawski

A University of Chicago-led consortium has received a five-year, $22.5 million grant from the National Institute of General Medical Sciences to study the dynamics of membrane proteins.

Comprising nearly 30 scientists from 14 institutions across four countries, the consortium will look to uncover the basic rules that govern the structure and function of several classes of membrane proteins, the consortium leader told ProteoMonitor this week.

Eduardo Perozo, who is also a professor of biochemistry and molecular biology at the University of Chicago Medical Center, noted that membrane proteins comprise 30 percent of the body's protein composition but account for roughly half of all drug targets, making them an important subject of study.

Traditionally the structure and function of membrane proteins have been investigated separately. The consortium's initiative, which will launch this month, is noteworthy because it will study them in tandem.

"The focus is on finding out the rules that link the static structures [of membrane proteins] to dynamics and function," Perozo said. The idea is "to look into how dynamics begets function based on structure."

The consortium has identified six different types of membrane proteins to investigate – ion channels, amino acid transporters, ABC-type transporters, APB-dependent pumps, hormone receptors, and proteins that mediate between transporters and ion channels.

The study will focus on proteins "for which structure is known and the function is interesting and physiologically relevant," Perozo said, noting that in the last several years there has been a significant increase in the number of membrane proteins whose structures have been determined.

Membrane proteins have traditionally been tricky to study due to the difficulty of extracting them with their structure and function intact. In addition, because they are typically large and biochemically unstable, it can be difficult to recreate the conditions required to study their activity.

"Membrane proteins are like extremely specialized opera divas," Perozo said. "They perform at a very high level, but once you take them out of their environment, they kind of fall apart."

"You have to combine the right conditions for extraction, the right conditions for stability, with the conditions [needed for them to] be studied spectroscopically or crystallographically," he added. "It's a bit of an art."

In addition to studying the proteins, the consortium will attempt to develop new tools and techniques to facilitate this study. There will be five core facilities, each tasked with developing a different set of tools for the initiative. The facilities will focus on computation; protein production; developing new probes for spectroscopic measurement and synthesizing proteins by chemical synthesis; building a system of phage display libraries; and developing toxins.

"We expect [the core facilities] to develop a number of very useful tools for research that will benefit the community at large," Perozo said.

The core facilities' work on developing tools and technologies will begin this month with the actual protein research starting in roughly three months.

It was not immediately clear whether the consortium plans to commercialize the technologies it develops, however, it does plan to make data and methods emerging from the initiative available on a public access website that Perozo anticipates will go live in September.

He said it will contain information on "material protocols, constructs, protein, and computational methods" as well as "new publications, new methods, material availability, and material requests."

Perozo said work will be divided among the researchers according to the dynamics that a protein exhibits and its particular function.

"There are systems [whose dynamic changes] are in the picoseconds to nanosecond range; systems that are in the microsecond to millisecond range; and systems that work in the millisecond to multi-millisecond range," Perozo said. "So that's one way" of dividing the research.

"Then layer on that another level of organization: systems where energy is transduced based on ligand binding; or energy conversion between ion gradients; or where binding of macromolecules leads to signal translocation," he added. "That's the parallel level of organization we have."

The researchers will be working under a "glue grant" from the NIGMS. According to the agency, this funding structure is intended "to make resources available for currently funded scientists to form research teams to tackle complex problems that are of central importance to biomedical science and to the mission of NIGMS, but that are beyond the means of any one research group."

The scientists applied two years ago in response to a call for proposals from the agency, Perozo said. While the initial grant is for five years, it can be renewed for an additional five years, although, he noted, it's not expected that all the researchers will be involved for the duration of the project.

"Not all the projects have an outlook of five to 10 years," he said. "Some will be shorter because they're closer to completion. What we hope to do is incorporate new projects and add new systems as some of the current projects mature and we reach the goals that were stated in the proposal."

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