The innate immune system detects invasive pathogens and activates defense mechanisms to eliminate them. Pathogens, however, employ a variety of tricks to block this process. A new study led by Karl-Peter Hopfner of Ludwig-Maximilians-Universitaet (LMU) in Munich shows how the measles virus thwarts the system, by means of a simple hairpin-like structure.
The innate immune system is the body's first line of defense against invasive pathogens and noxious chemicals. Essentially the system consists of an array of receptors that recognize particular molecular conformations which are characteristic of pathogenic organisms and viruses. Among the classes of molecules bound by these receptors are viral nucleic acids, which are bound specifically by so-called RIG-I-like receptors in the cytoplasm of infected cells. One of these is MDA5, which polymerizes into filaments on long double-stranded RNAs that indicate the presence of RNA viruses. RIG-I itself binds to shorter terminal segments of viral RNAs.
However, viruses have come up with a plethora of ways to avoid triggering immune defense measures. "The virus that causes measles, for instance, produces a so-called V protein, which binds specifically to MDA5 and one other RIG-I-like receptor, and thus impairs recognition of virus-infected cells by the adaptive immune system, although it does not inhibit RIG-I itself," says Professor Karl-Peter Hopfner of LMU's Gene Center. Indeed this kind of competition between viral and cellular proteins largely determines the distribution and - above all - the virulence of viral pathogens.
A hairpin opens up the receptor
"We have been able to crystallize the complex formed by the V protein and MDA5 for the first time, and have determined its three-dimensional structure in detail," Hopfner reports. This structure also permitted Hopfner's team, in collaboration with LMU virologist Professor Karl-Klaus Conzelmann, to clarify the mode of action of the V protein. The analysis revealed that it inserts a hairpin loop into the core secondary structure of MDA5, unfolding the protein and allowing V to bind to a segment that is normally buried in the interior of the molecule. This in turn prevents MDA5 from forming filaments and signaling the presence of viral RNA.
This finding was completely unexpected, and explains why MDA5, but not RIG-I, is inhibited by the V protein: This internal sequence is different in RIG-I and this is the reason why RIG-I is not targeted by the viral product. "Our work provides a detailed insight into the mechanisms viral proteins use to inhibit host protein function. It may also open opportunities for new therapeutic interventions," Hopfner concludes.
Ludwig-Maximilians-Universit�t M�nchen: http://www.uni-muenchen.de
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Mother deer rushed towards the infant distress calls of seals, humans and even bats, suggesting that these mammals share similar emotions
In the forests of eastern Australia, a squadron of social spiders faces off against an army of the world's most dangerous ants in a pitched battle for survival
Contrary to some earlier projections, the world's population will soar through the end of the 21st century thanks largely to sub-Saharan Africa's higher-than-expected birth rates, United Nations and other population experts said on Thursday.
Archaeologists got to the root of an ancient hairstyle when they unearthed a 3,300-year-old body with 70 hair extensions
A major international study finds that killings among chimpanzees result from normal competition, not human interference.
Clownfish travel hundreds of kilometres, but it is the larvae rather than the adults that migrate
U.S. government researchers working with divers and sonar equipment have located the wrecks of what they dubbed "forgotten ghost ships" in waters just outside San Francisco's Golden Gate strait.
"It's spooky," a Clearwater, Fla., fisherman said, comparing the toxic algae bloom to "boiled red Georgia clay"
Physicist Danielle Bassett has been awarded a MacArthur Fellowship based on her work studying the human brain. She talks with Melissa Block about the advances it may lead to.
A team of researchers are using multispectral imaging to uncover hidden text on a 1491 Martellus map, one of the most important maps in history. Lead researcher Chet Van Duzer thinks the discoveries will allow historians and scholars to see just how the map influenced cartography in its time.