Immune system foiled by a hairpin

January 22, 2013

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 shows how the measles virus thwarts the system, by means of a simple hairpin-like structure.

The is the body's first line of defense against invasive pathogens and . Essentially the system consists of an array of receptors that recognize particular molecular conformations which are characteristic of 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 , 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 largely determines the distribution and - above all - the virulence of .

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 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.

Explore further: Research provides unprecedented insight into fighting viral infections

More information: Science, 17 January 2013. www.sciencemag.org/content/ear … nce.1230949.abstract

Related Stories

Research provides unprecedented insight into fighting viral infections

September 29, 2011
Researchers at Rutgers and UMDNJ-Robert Wood Johnson Medical School have determined the structure of a protein that is the first line of defense in fighting viral infections including influenza, hepatitis C, West Nile, rabies, ...

Who goes there? Novel complex senses viral infection

June 23, 2011
Double-stranded (ds) RNA viruses are a diverse group of viruses that include rotaviruses, a common cause of gastroenteritis. The ability of the immune system to detect and destroy viruses is critical for human health and ...

Recommended for you

Genetic immune deficiency could hold key to severe childhood infections

July 18, 2017
A gene mutation making young children extremely vulnerable to common viruses may represent a new type of immunodeficiency, according to a University of Queensland researcher.

What are the best ways to diagnose and manage asthma?

July 18, 2017
What are the best ways to diagnose and manage asthma in adults? This can be tricky because asthma can stem from several causes and treatment often depends on what is triggering the asthma.

Large multi-ethnic study identifies many new genetic markers for lupus

July 17, 2017
Scientists from an international consortium have identified a large number of new genetic markers that predispose individuals to lupus.

Study finds molecular explanation for struggles of obese asthmatics

July 17, 2017
A large, bouquet-shaped molecule called surfactant protein A, or SP-A, may explain why obese asthma patients have harder-to-treat symptoms than their lean and overweight counterparts, according to a new study led by scientists ...

Team identifies potential cause for lupus

July 14, 2017
Leading rheumatologist and Feinstein Institute for Medical Research Professor Betty Diamond, MD, may have identified a protein as a cause for the adverse reaction of the immune system in patients suffering from lupus. A better ...

Immunosuppression underlies resistance to anti-angiogenic therapy

July 14, 2017
A Massachusetts General Hospital (MGH) research team has identified a novel mechanism behind resistance to angiogenesis inhibitors - drugs that fight cancer by suppressing the formation of new blood vessels. In their report ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.