SAN FRANCISCO--Among the most important molecules in biology are proteins that wedge themselves into the fatty membranes surrounding cells. As gatekeepers, they detect key compounds outside the cell and determine which should be allowed inside. Studying these receptor molecules in detail is extremely difficult, because they almost always stop working if removed from the cell membrane. But now a team has found a way to put them on display while making it seem as if they've never left home.
At a meeting here last week of the Materials Research Society, Stephen Sligar, a biochemist at the University of Illinois, Urbana-Champaign, reported that he and his colleagues have ensconced individual membrane-bound receptors in lipid-based nanodiscs. Like natural cell membranes, the discs are composed of two back-to-back layers of phospholipid molecules, each sporting water-friendly head groups and long, oily water-repellant tails. To keep the discs flat, the team fashioned a belt of proteins that surround the disc like the seaweed wrapper on a sushi roll.
To demonstrate that receptors still function inside the nanodisc, Sligar's graduate student Andrew Leitz turned to a well-known protein: the β2 adrenergic receptor (β2AR), a target of heart drugs called beta blockers. The researchers dosed β2AR-containing discs with a small druglike compound that normally binds to the portion of the receptor facing out of the cell. The binding triggers the β2AR to change shape and release a "G" protein, which in cells binds to the inside end of the receptor. Using radiolabeled compounds, the group found that the receptors in the discs traced the same key steps.
"It's a very cool technique," says Robert Hamers, a chemist at the University of Wisconsin, Madison. "I can see all kinds of applications for something like this." Hamers says nanodiscs could shed light on the biochemical behavior of a host of membrane proteins that have escaped detailed understanding. In time the method may also make it possible to crystallize membrane proteins to obtain atomic-level maps of their structure using x-ray crystallography, another long-elusive goal.
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