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A Clamp for Emerging Flu Viruses - Researchers in Freiburg and Berlin Unravel Secret of Innate Immune Response

  When the human body becomes infected with new influenza viruses, the immune system rapidly activates an inborn protective mechanism to inhibit the intruding pathogen. A protein known as Mx plays an important role in this process, keeping the spread of viruses in check. Exactly how Mx accomplishes this task was previously unknown. Now virologists from the Institute of Medical Microbiology at the Freiburg University Medical Center and biochemists from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch, Germany, have unraveled the structure of the Mx protein and are able to explain how it develops its anti-viral effect (Nature, doi: 10.1038/nature08972)*.

New
influenza viruses jump from animals to humans with alarming frequency, as
evidenced by the H5N1 bird flu virus or, more recently, with the swine flu
virus. Although humans usually do not have any preexisting immunity to such
pathogens, they are not completely unprotected against the invaders. The human
body can rapidly mobilize a defense strategy which prevents the influenza
viruses from proliferating unchecked in the body.

An
essential element of this protection is a protein, known as Mx (short for
myxovirus resistance), produced by the body which recognizes many viruses and
prevents them from replicating inside infected cells. Under normal conditions
this protective protein is not present in the cell at all, but after infection
it can be produced in large quantities. The order to produce this protein Mx is
made by the signaling protein interferon, which is excreted by infected cells
and alarms the organism of the virus infection.

Mx is a
molecular machine which does not develop its full power until the individual
molecules have joined to form a ring-structured macromolecular network. A central
element of the formation of these ring structures is the special part of Mx
known as the stalk.

Scientists
have attempted to describe the structure of this stalk for years. The
virologists Otto Haller, Alexander von der Malsburg, and Georg Kochs in Freiburg and the structural biologists Oliver Daumke,
Song Gao, Susann Paeschke, and Joachim Behlke from MDC in Berlin-Buch have now
unraveled the secret of the stalk structure of Mx at the atomic level. This structure explains the
composition of Mx and allows scientists to conduct tests to make predictions
concerning the mode of action of the antiviral molecule. 

In
combination with findings from earlier biochemical studies, the results of this
study make it clear that the stalk structure of Mx functions as a kind of clamp
which restrains and deactivates important components of the influenza virus in
the infected cell. The fact that new forms of flu can lead to epidemics or even
pandemics in spite of this defense mechanism is due to the power and aggressiveness
of these pathogens.

The
researchers are confident that their new findings about the protective Mx
protein will form the basis for the development of new antiviral drugs for
combating dangerous influenza viruses. Moreover, they are also certain that
this new knowledge about the function of Mx will increase their understanding
of other members of this family of proteins.

*Structural basis of oligomerisaton in the stalk region of dynamin-like
MxA

Song Gao1,2, Alexander von der
Malsburg3, Susann Paeschke1, Joachim Behlke1,
Otto Haller3, Georg Kochs3, Oliver Daumke1

1Max DelbrückCenter
for Molecular Medicine, Crystallography, Robert-Rössle-Strasse 10, 13125 Berlin, Germany

2Institute for
Chemistry and Biochemistry, Free University Berlin,
Takustrasse 3, 14195 Berlin,
Germany

3Department of
Virology, Institute of Medical Microbiology and Hygiene, University of Freiburg,
Hermann-Herderstrasse 11, 79104 Freiburg,
Germany

Molecular model for the ring-shaped oligomer of the Mx protein. In an infected cell this ring clamps components of the influenza virus resulting in the inhibition of virus replication. (Model: Oliver Daumke/Copyright: MDC)

Dr. Oliver Daumke
Max Delbrück Center for
Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Strasse 10
13125 Berlin
Phone:    +49-30-94 06-34 25
Fax:    +4930-94 06-38 14
e-mail: oliver.daumke@mdc-berlin.de
http://www.mdc-berlin.de/daumke
Prof. Dr. Otto Haller
Freiburg University Medical Center
Institute of Medical Microbiology
and Hygiene; Department of Virology
Hermann-Herder-Str. 11
79104 Freiburg
Phone: +49 761 203 65 34
Fax:     +49 761 203 66 26
e-mail: otto.haller@uniklinik-freiburg.de
http://www.virologie-freiburg.de