Featured Research

from universities, journals, and other organizations

Scientists crack mystery of protein's dual function

Date:
December 14, 2009
Source:
Scripps Research Institute
Summary:
Researchers have solved a 10-year-old mystery of how a single protein from an ancient family of enzymes can have two completely distinct roles in the body. In addition to providing guidance for understanding other molecules in the family, the research supplies a theoretical underpinning for the protein's possible use for combating diseases including cancer and macular degeneration.

Researchers at The Scripps Research Institute have solved a 10-year-old mystery of how a single protein from an ancient family of enzymes can have two completely distinct roles in the body. In addition to providing guidance for understanding other molecules in the family, the research supplies a theoretical underpinning for the protein's possible use for combating diseases including cancer and macular degeneration.

The research was published in the December 13, 2009 advance, online issue of the high-impact journal Nature Structural and Molecular Biology.

The scientists, led by Scripps Research Associate Professor Xiang-Lei Yang, focused on a molecule called human tryptophanyl-tRNA synthetase (TrpRS), finding that it contains a "functional switch" that enables it to perform two different functions. In one of its forms, the molecule acts to facilitate protein synthesis. In the second form, the same molecule works to inhibit the formation of new blood vessels -- an effect that, if successfully harnessed, could be medically useful.

"I'm very excited about these findings," said Yang. "This piece of work provides a very deep mechanistic understanding. It has really shown that the activity of this tRNA synthetase is of biological significance and that it's a good example of the many, many different functions that have been found with the tRNA synthetase family."

One Enzyme, Two Functions

For some time, scientists have known that the aminoacyl tRNA synthetase family is composed of 20 ancient enzymes that attach the correct amino acid to a tRNA as the first step in the synthesis of proteins.

The mystery of the protein family's dual functionality, however, was born about a decade ago, with the publication of a 1999 paper in the journal Science by Paul Schimmel, who is Ernest and Jean Hahn Professor of Molecular Biology and Chemistry and a member of The Skaggs Institute for Chemical Biology at Scripps Research, in collaboration with a member of his lab at that time, Keisuke Wakasugi.

In the 1999 paper, Wakasugi and Schimmel showed that a member of the human aminoacyl-tRNA synthetase family, tyrosyl-tRNA synthetase (TyrRS), did more than adding the amino acid tyrosine to a protein chain during protein synthesis. In addition, a fragment of the protein could function to attract immune cells and to stimulate the growth of blood vessels.

The findings were met with astonishment and some skepticism in the scientific community.

Soon afterward, however, the Schimmel lab showed that another member of the family, TrpRS, also had a dual function. In addition to its role adding the amino acid tryptophan to a protein chain during protein synthesis, a fragment of TrpRS could inhibit new blood vessel formation.

Since that time, there has been considerable therapeutic interest in TyrRS, TrpRS, and other members of the aminoacyl-tRNA synthetase family. As a pro-angiogenic factor, the TyrRS fragment could be useful in diseases where growth of blood vessels is desirable, such as in some forms of heart disease or peripheral artery disease. Likewise, the TrpRS fragment's anti-angiogenic effects could help patients reduce undesirable blood vessel growth in diseases such as cancer and a great many eye diseases that lead to catastrophic vision loss.

In fact, fragments of TrpRS were used as part of a study led by Scripps Research Professor Martin Friedlander that successfully halted the progression in animal models of highly vascular brain tumor and neovascular eye disease (PNAS 2007 104:967-972).

Despite the interest in tRNA synthetases, however, no one has been able to figure out exactly how they perform their different roles -- until now.

Mystery Mechanism Revealed

In the current study, the research team used a combination of techniques including structural modeling analysis, mutagenesis, and cell-based functional studies to unravel the secrets of TrpRS.

The scientists identified the specific molecular changes that enabled TrpRS to perform one function or another.

In the study, the scientists show that, for its role in protein synthesis, TrpRS is typically in its full-length form. This form of the molecule contains a tryptophan-binding pocket that enables it to bind with the amino acid and shepherd it to where it is needed in protein synthesis.

In the second active form, however, the protein must first be broken into fragments by the body, creating a piece called T2-TrpRS. With the removal of the end of the full-length protein (the N-domain), new grooves in the T2-TrpRS protein fragment are revealed. Containing the now-exposed tryptophan-binding pocket, the grooves fit together with side chains of another molecule, VE-cadherin -- known to be indispensable for proper vascular development.

Interestingly, the new study found that tryptophan acts to inhibit of the vasculature function of TrpRS, locking the protein into its protein-synthesis form.

Therapeutic Potential

Yang notes that the therapeutic potential of TrpRS and other tRNA synthetases are particularly good because they normally exist in abundant amounts in the body.

"Naturally, you'd imagine the body's tolerance for such a protein is pretty good," she said, "and we could use the activated form of the molecule."

In addition, Yang points out that TrpRS is intriguing because it does not effect existing blood vessel growth, only new blood vessel formation, reducing the odds of negative side effects from its use.

This work was supported by the National Institutes of Health, and by a fellowship from the National Foundation for Cancer Research.


Story Source:

The above story is based on materials provided by Scripps Research Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Zhou et al. Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality. Nature Structural & Molecular Biology, 2009; DOI: 10.1038/nsmb.1706

Cite This Page:

Scripps Research Institute. "Scientists crack mystery of protein's dual function." ScienceDaily. ScienceDaily, 14 December 2009. <www.sciencedaily.com/releases/2009/12/091213164713.htm>.
Scripps Research Institute. (2009, December 14). Scientists crack mystery of protein's dual function. ScienceDaily. Retrieved July 23, 2014 from www.sciencedaily.com/releases/2009/12/091213164713.htm
Scripps Research Institute. "Scientists crack mystery of protein's dual function." ScienceDaily. www.sciencedaily.com/releases/2009/12/091213164713.htm (accessed July 23, 2014).

Share This




More Health & Medicine News

Wednesday, July 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Courts Conflicted Over Healthcare Law

Courts Conflicted Over Healthcare Law

AP (July 22, 2014) Two federal appeals courts issued conflicting rulings Tuesday on the legality of the federally-run healthcare exchange that operates in 36 states. (July 22) Video provided by AP
Powered by NewsLook.com
Why Do People Believe We Only Use 10 Percent Of Our Brains?

Why Do People Believe We Only Use 10 Percent Of Our Brains?

Newsy (July 22, 2014) The new sci-fi thriller "Lucy" is making people question whether we really use all our brainpower. But, as scientists have insisted for years, we do. Video provided by Newsy
Powered by NewsLook.com
Scientists Find New Way To Make Human Platelets

Scientists Find New Way To Make Human Platelets

Newsy (July 22, 2014) Boston scientists have discovered a new way to create fully functioning human platelets using a bioreactor and human stem cells. Video provided by Newsy
Powered by NewsLook.com
Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins