Discovery may be first plant cell surface molecule that halts cell proliferation

Protein contains both ’on’ and ’off’ switches

University of North Carolina at Chapel Hill scientists have discovered a unique protein on the surface membrane of plant cells, one that apparently contains both “on” and “off” molecular switches. Apart from its unique structure, the protein may be the first cell surface membrane receptor ever discovered in plants that regulates a key protein complex involved in cell growth and division. Known as the heterotrimeric G protein complex, it also is present in mammalian cells, including human.

The protein, known as AtRGS1, regulates the process of cell proliferation by turning the G protein complex off. A report of the discovery appears in today’s (Sept. 19) issue of the journal Science.

The protein was discovered in Arabidopsis thaliana, a wild mustard weed. Completion of the Arabidopsis genome sequence in 2000, the first for a higher plant, made it ideal for molecular investigation such as this. In addition, this small weed has homologues or counterparts of many important human proteins, including some involved in diseases, such as cystic fibrosis and cancer.

“We have identified the first and a truly novel regulator of G protein signaling, or RGS signaling protein, in Arabidopsis,” said Dr. Jin-Gui Chen, senior research associate in the department of biology and the report’s first author. “This finding can be considered a breakthrough in G protein signaling.”

Roughly 800 types of these cell receptors exist in human cells, said plant cell biologist Dr. Alan M. Jones, a senior study author and professor of biology in UNC’s College of Arts and Sciences.

“These are the molecular targets for about half of the drugs in use today worldwide, which account for $9 billion a year in sales.” Teasing out the complexities of how signals are transduced into action within cells also holds implications for agriculture. “The new RGS protein’s function in the G protein signaling pathway may give us a handle on how fast plant organs can produce cells,” said Jones.

“Indeed, this particular pathway is a growth pathway, and now we have another player [AtRGS1] we can utilize to bioengineer crops.” Previous studies of mammalian cells had provided hints that G protein coupled receptors and RGS proteins are intimately linked functionally, said the other senior author of the study, Dr. David P. Siderovski. He is an assistant professor of pharmacology and a member of UNC’s Lineberger Comprehensive Center, part of UNC’s School of Medicine.

“And this study is the ultimate proof because they are intimately linked structurally,” he added. “This really sets the paradigm clearly in the minds of all of us studying this signaling. For a long time there have been hints of receptor-specific recruitment of these RGS proteins. But plants have really slapped us awake to this because they’re one polypeptide; they’re actually conjoint.”

The new study exemplifies UNC’s research strength in G protein signaling, including RGS proteins. Siderovski and Dr. Henrik G. Dohlman, associate professor of biochemistry and biophysics, were the first to independently discover this class of proteins nearly eight years ago.

Dohlman found the first such protein in yeast, while Siderovski had found similar proteins in humans.

Jones, who for many years has been studying the plant components equivalent to the G protein complex in mammals, asked Siderovski to explore the Arabidopsis data base for a G protein coupled receptor. In searching through protein sequences on a computer screen, Siderovski said he stumbled upon a divergent form of RGS protein in Arabidopsis, one with features of both a cell-surface receptor and an RGS protein. Dohlman, whose laboratory tested the function of the new protein in yeast, said a common theme in biology is that every ’on’ switch has an ’off’ switch. “What’s unique about this particular protein is it seems to contain elements of both the ’on’ switch and ’off’ switch in the same molecule. And this is unprecedented,” he said.

“The classic paradigm is you have a cell surface receptor that activates a pathway by binding some molecule, such as calcium or a hormone,” said Jones. “Here we have a ’CatDog’ phenomenon,” he added, referring to a popular TV cartoon series, “a putative receptor that has the structural features of both an activator and an RGS-like deactivator.”

Still, the researchers said, two interpretations may operate here. One is that the switches are simply physically linked. Or it could be that the ’off’ switch and the ’on’ switch are each regulated by external signals. They agree, however, that either scenario is extremely exciting.

“I think this opens up a new paradigm that may not be specific or unique to the plant cell. I would not be surprised if we find it in human cells,” said Jones.

Other co-authors are Dr. Francis S. Willard, from the department of pharmacology and the Lineberger Center; Dr. Scott A. Chasse, a trainee with Dohlman from biochemistry and biophysics; and Jirong Huang and Jiansheng Liang, from the department of biology. Support for this research came from the National Institute of General Medical Sciences and the National Science Foundation via grants awarded to Siderovski, Dohlman and Jones.

Note: Contact Jones at (919) 962-6932 or alan_jones@unc.edu. Contact Siderovski at (919) 843-9363 or david_siderovski@med.unc.edu. Contact Dohlman at (919) 843-6894 or henrik_dohlman@med.unc.edu.

School of Medicine contact: Les Lang, (919) 843-9687 or llang@med.unc.edu