Featured Research

from universities, journals, and other organizations

It slices, it dices, and it protects the body from harm: 3-D structure of enzyme that helps defend against bacteria

Date:
February 28, 2014
Source:
Princeton University
Summary:
An essential weapon in the body's fight against infection has come into sharper view. Researchers have discovered the 3-D structure of an enzyme that cuts to ribbons the genetic material of viruses and helps defend against bacteria. The discovery of the structure of this enzyme, a first-responder in the body's "innate immune system," could enable new strategies for fighting infectious agents and possibly prostate cancer and obesity. "This work illustrates the wonderful usefulness of doing both crystallography and careful kinetic and enzymatic studies at the same time," said one scientist.

Researchers at Princeton have deciphered the 3-D structure of RNase L, an enzyme that slices through RNA and is a first responder in the innate immune system. The structure contains two subunits, represented in red as two parts of a pair of scissors.
Credit: Illustration by Sneha Rath. Inset courtesy of Science.

An essential weapon in the body's fight against infection has come into sharper view. Researchers at Princeton University have discovered the 3D structure of an enzyme that cuts to ribbons the genetic material of viruses and helps defend against bacteria.

The discovery of the structure of this enzyme, a first-responder in the body's "innate immune system," could enable new strategies for fighting infectious agents and possibly prostate cancer and obesity. The work was published Feb. 27 in the journal Science.

Until now, the research community has lacked a structural model of the human form of this enzyme, known as RNase L, said Alexei Korennykh, an assistant professor of molecular biology and leader of the team that made the discovery.

"Now that we have the human RNase L structure, we can begin to understand the effects of carcinogenic mutations in the RNase L gene. For example, families with hereditary prostate cancers often carry genetic mutations in the region, or locus, encoding RNase L," Korennykh said. The connection is so strong that the RNase L locus also goes by the name "hereditary prostate cancer 1." The newly found structure reveals the positions of these mutations and explains why some of these mutations could be detrimental, perhaps leading to cancer, Korennykh said. RNase L is also essential for insulin function and has been implicated in obesity.

The Princeton team's work has also led to new insights on the enzyme's function.

The enzyme is an important player in the innate immune system, a rapid and broad response to invaders that includes the production of a molecule called interferon. Interferon relays distress signals from infected cells to neighboring healthy cells, thereby activating RNase L to turn on its ability to slice through RNA, a type of genetic material that is similar to DNA. The result is new cells armed for destruction of the foreign RNA.

The 3D structure uncovered by Korennykh and his team consists of two nearly identical subunits called protomers. The researchers found that one protomer finds and attaches to the RNA, while the other protomer snips it.

The initial protomer latches onto one of the four "letters" that make up the RNA code, in particular, the "U," which stands for a component of RNA called uridine. The other protomer "counts" RNA letters starting from the U, skips exactly one letter, then cuts the RNA.

Although the enzyme can slice any RNA, even that of the body's own cells, it only does so when activated by interferon.

"We were surprised to find that the two protomers were identical but have different roles, one binding and one slicing," Korennykh said. "Enzymes usually have distinct sites that bind the substrate and catalyze reactions. In the case of RNase L, it appears that the same exact protein surface can do both binding and catalysis. One RNase L subunit randomly adopts a binding role, whereas the other identical subunit has no other choice but to do catalysis."

To discover the enzyme's structure, the researchers first created a crystal of the RNase L enzyme. The main challenge was finding the right combination of chemical treatments that would force the enzyme to crystallize without destroying it.

After much trial and error and with the help of an automated system, postdoctoral research associate Jesse Donovan and graduate student Yuchen Han succeeded in making the crystals.

Next, the crystals were bombarded with powerful X-rays, which diffract when they hit the atoms in the crystal and form patterns indicative of the crystal's structure. The diffraction patterns revealed how the atoms of RNase L are arranged in 3D space.

At the same time Sneha Rath, a graduate student in Korennykh's laboratory, worked on understanding the RNA cleavage mechanism of RNase L using synthetic RNA fragments. Rath's results matched the structural findings of Han and Donovan, and the two pieces of data ultimately revealed how RNase L cleaves its RNA targets.

Han, Donovan and Rath contributed equally to the paper and are listed as co-first authors.

Finally, senior research specialist Gena Whitney and graduate student Alisha Chitrakar conducted additional studies of RNase L in human cells, confirming the 3D structure.

Now that the human structure has been solved, researchers can explore ways to either enhance or dampen RNase L activity for medical and therapeutic uses, Korennykh said.

"This work illustrates the wonderful usefulness of doing both crystallography and careful kinetic and enzymatic studies at the same time," said Peter Walter, professor of biochemistry and biophysics at the University of California-San Francisco School of Medicine. "Crystallography gives a static picture which becomes vastly enhanced by studies of the kinetics."


Story Source:

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


Journal Reference:

  1. Y. Han, J. Donovan, S. Rath, G. Whitney, A. Chitrakar, A. Korennykh. Structure of Human RNase L Reveals the Basis for Regulated RNA Decay in the IFN Response. Science, 2014; DOI: 10.1126/science.1249845

Cite This Page:

Princeton University. "It slices, it dices, and it protects the body from harm: 3-D structure of enzyme that helps defend against bacteria." ScienceDaily. ScienceDaily, 28 February 2014. <www.sciencedaily.com/releases/2014/02/140228210604.htm>.
Princeton University. (2014, February 28). It slices, it dices, and it protects the body from harm: 3-D structure of enzyme that helps defend against bacteria. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2014/02/140228210604.htm
Princeton University. "It slices, it dices, and it protects the body from harm: 3-D structure of enzyme that helps defend against bacteria." ScienceDaily. www.sciencedaily.com/releases/2014/02/140228210604.htm (accessed July 31, 2014).

Share This




More Matter & Energy News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Britain Testing Driverless Cars on Roadways

Britain Testing Driverless Cars on Roadways

AP (July 30, 2014) British officials said on Wednesday that driverless cars will be tested on roads in as many as three cities in a trial program set to begin in January. Officials said the tests will last up to three years. (July 30) Video provided by AP
Powered by NewsLook.com
Amid Drought, UCLA Sees Only Water

Amid Drought, UCLA Sees Only Water

AP (July 30, 2014) A ruptured 93-year-old water main left the UCLA campus awash in 8 million gallons of water in the middle of California's worst drought in decades. (July 30) Video provided by AP
Powered by NewsLook.com
Smartphone Powered Paper Plane Debuts at Airshow

Smartphone Powered Paper Plane Debuts at Airshow

AP (July 30, 2014) Smartphone powered paper airplane that was popular on crowdfunding website KickStarter makes its debut at Wisconsin airshow (July 30) Video provided by AP
Powered by NewsLook.com
U.K. To Allow Driverless Cars On Public Roads

U.K. To Allow Driverless Cars On Public Roads

Newsy (July 30, 2014) Driverless cars could soon become a staple on U.K. city streets, as they're set to be introduced to a few cities in 2015. Video provided by Newsy
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