Skip Over Navigation Links

NIH Research Matters

April 29, 2013

Arrestin Developments

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 -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.

Related Links:

Reference: Nature. 2013 Apr 21. doi: 10.1038/nature12120. [Epub ahead of print]. PMID: 23604254

Funding: NIHs National Institute of Neurological Disorders and Stroke (NINDS), National Heart, Lung and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS), along with the Stanford Medical Scientist Training Program, the American Heart Association, the National Science Foundation, the Mathers Foundation, Coordenação de Aperfeiçoamentode Pessoal de Nível Superior and the Howard Hughes Medical Institute.

Contact Us

E-mail: nihresearchmatters@od.nih.gov

Mailing Address:
NIH Research Matters
Bldg. 31, Rm. 5B64A, MSC 2094
Bethesda, MD 20892-2094

About NIH Research Matters

Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

This page last reviewed on April 29, 2013

Social Media Links