Researchers visualized a key step in how signals from outside the cell are muted within. The finding gives insight into the complex system that controls how all the cells in our bodies behave. This knowledge could have implications in the design of many drugs.
Activated ß-arrestin-1 (yellow) binds a G-protein coupled receptor (green) that crosses the cell membrane (gray).Illustration by Shukla et al., courtesy of Nature.
G-protein coupled receptors (GPCRs) are a large family of proteins, with hundreds of different members that allow cells to sense light, hormones or other molecules. GPCRs span cell membranes and carry signals from the outside in, so the cell can react. Once activated, GPCRs can trigger a cascade of responses inside the cell. They control countless essential body functions and are the target of many drugs.
GPCRs are notoriously difficult to study in 3-D detail. Their large, floppy and unwieldy structures make them troublesome to prepare for X-ray crystallography, which can detect atomic features but requires the formation of uniform crystals. The first GPCR structure to be solved was the light-sensing protein rhodopsin, isolated from a cow’s retina. Since then, innovations have allowed researchers to solve the X-ray crystal structures of more GPCRs.
Drs. Robert J. Lefkowitz of Duke University and Brian K. Kobilka of Stanford University were awarded the 2012 Nobel Prize in Chemistry for their studies of GPCRs. In their latest work, the researchers collaborated to focus on arrestins. These molecules bind to GPCRs within the cell to dampen or stop their signals. Arrestins can also activate numerous signaling pathways.
The researchers were studying the interactions between β-arrestin-1 and a human GPCR called the V2 vasopressin receptor. However, they had trouble forming well-ordered crystals that captured the molecules’ interactions. They thus searched for a synthetic antibody fragment that could stabilize β-arrestin-1 in its active state bound to a segment of the receptor. The work was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), National Heart, Lung and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS).
The scientists were able to capture β-arrestin-1 in its active state and form crystals to determine its structure, as reported online in Nature on April 21, 2013. Compared to previously determined inactive state structures, activated β-arrestin-1 has pronounced structural changes. These include 2 domains of the protein that are twisted relative to one another, and a major change in the location of another part of the protein.
In the same issue of Nature, a team led by researchers in Germany published the structure of another arrestin from the bovine eye called arrestin p44. These scientists found similar changes between the active and inactive states of arrestin p44.
Together, these findings suggest that arrestins may share similar activated states. Further studies of entire GPCR–arrestin interactions will yield more insight into how GPCRs achieve such a breadth of signaling complexity.
“It’s important to understand how this extraordinary family of receptors work,” says Lefkowitz. “This is the kind of finding that answers a basic curiosity, but can also be of benefit if we can develop new drugs or improve the ones we have.”
By Harrison Wein, Ph.D.
* The above story is reprinted from materials provided by National Institutes of Health (NIH)
** The National Institutes of Health (NIH) , a part of the U.S. Department of Health and Human Services, is the nation’s medical research agency—making important discoveries that improve health and save lives. The National Institutes of Health is made up of 27 different components called Institutes and Centers. Each has its own specific research agenda. All but three of these components receive their funding directly from Congress, and administrate their own budgets.