|
From
Medical News Today
January 6, 2006
Molecular Structure Of Viral
Protein, Parainfluenza Virus 5 Fusion
(F) Protein, Identified By Scientists At
Northwestern University
Main Category:
Biology / Biochemistry News
Article Date: 06 Jan 2006 - 0:00am (PDT)
Scientists at Northwestern University
have determined the molecular structure
of a viral protein, the parainfluenza
virus 5 fusion (F) protein. The
parainfluenza virus 5 is part of a
family of viruses (paramyxoviruses) that
causes everything from pneumonia, croup
and bronchiolitis to cold-like illness
and is responsible for many
hospitalizations and deaths each year.
The results will be published Jan. 5 by
the journal Nature.
Details of the protein's structure in
its metastable state -- the state of the
protein on the virus surface responsible
for infecting cells -- has significant
implications for developing improved
protein-based vaccines, designing novel
anti-viral agents and understanding the
entry mechanisms of other viruses.
Knowing the structure of the F protein
will aid understanding of all members of
the paramyxovirus family, which are
among the most significant human and
animal pathogens, causing both
respiratory and systemic disease.
"The development of antiviral drugs is
helped by knowledge of the structure,
shape and mechanism of the target
molecules, which is what we can now
provide for the F protein," said
Theodore S. Jardetzky, professor of
biochemistry, molecular biology and cell
biology, who co-led the study. "Knowing
how the virus gets into the cell will
allow us to better inhibit this key part
of the viral life cycle."
Tens of thousands of different proteins
are at work in the human body, each
folded into a very specific shape to do
its job properly. Most proteins have
just one shape for their lifetimes, but
a handful -- in particular, proteins
associated with enveloped viruses such
as HIV, influenza virus and the
paramyxoviruses -- have two dramatically
different shapes, one before the virus
attacks and enters a cell and one after.
The parainfluenza virus 5 fusion protein
is one of these. It is the change of the
fusion protein from the initial
metastable state to the post-virus entry
state that drives the fusion of viral
and cellular membranes, permitting entry
of the viral genome into the cell.
"What we've learned about the structure
of the parainfluenza virus 5 fusion
protein will be directly applicable to
the whole family of paramyxoviruses,"
said virologist Robert A. Lamb, John
Evans Professor of Biochemistry,
Molecular Biology and Cell Biology and
co-leader of the study. "The family
includes viruses that cause measles,
mumps,
bronchitis, pneumonia, canine
distemper, croup and Newcastle disease,
which kills chickens. Measles still
causes huge numbers of deaths worldwide.
And while HIV, influenza and SARS are
not in the same family, the viruses do
share a mechanism similar to that used
by paramyxoviruses for entering the host
cell."
The parainfluenza virus 5 is also
closely related to two recently
discovered and deadly viruses called
Hendra and Nipah viruses, which are
classified as select agents of concern
for biodefense.
The pre-fusion structure of the F
protein combined with the structure of
the protein in its post-fusion state,
which was determined and reported
earlier in 2005 by this same research
team, gives scientists a complete
picture of how the paramyxovirus F
protein works to infect the cell.
The F protein belongs to a group of
fusion proteins (class I) that exist in
two states: the metastable or pre-fusion
state and the post-fusion state. This is
only the second time that both the pre-
and post-fusion structures have been
determined for a class I viral fusion
protein. The first was for the influenza
virus, completed in 1994. While a lot of
research is currently being conducted on
the HIV fusion protein, its two
structures -- and an understanding of
how the protein works -- remain
incomplete.
"The protein we studied," explained
Lamb, an Investigator for the Howard
Hughes Medical Institute, "is
sequestered on the virus and is
responsible for bringing about a
membrane merger or fusion of the viral
and cellular membranes. The protein
opens the inside of the virus to the
inside of the cell, delivering the
viruses genetic information into the
cytoplasm of the cell to infect it."
In the process the protein moves from
its first folded state, the metastable
state (pre-fusion), to its second, final
and very stable state (post-fusion),
undergoing a dramatic change of shape.
"The protein in its metastable state has
a very specific job to do -- to enable
infection of the cell -- and it does
this by essentially acting as a harpoon
that shoots into the cell's membrane to
bring about the fusion," said Jardetzky.
"The metastable protein is a
one-time-use machine," said Lamb. "It
does its work and then it's finished,
spent. And you want the protein to be
triggered at the right time and in the
right place for fusion: when the virus
binds to the cell's surface."
The research team determined the
pre-fusion structure by imaging crystals
of the protein, using the extremely
brilliant X-rays produced by the
Advanced Photon Source (APS) synchrotron
at Argonne National Laboratory in
Illinois and at the Howard Hughes
Medical Institute beamlines at the
Advanced Light Source in Berkeley,
Calif.
First the researchers had to make the
protein, which included pulling a
scientific trick on the protein to get
it to fold properly and keep it in its
metastable state. Because the molecules
of the protein are so small they could
not be imaged directly. Instead, the
researchers used many of these molecules
to create a crystal that could be
imaged.
Using the method of X-ray diffraction,
they bombarded the crystal with X-rays,
which bounced off the atoms within the
crystal. By collecting and analyzing
this information, Jardetzky, Lamb and
their colleagues determined the location
of each atom within the structure.
Jardetzky credits the very high
intensity X-rays for enabling the
researchers to image the structure at
2.85 angstroms. (An angstrom is one
ten-billionth of a meter, or about
one-hundred-millionth of an inch.) This
resolution was critical for an accurate
picture of how the 10,805 atoms in the
structure are assembled. In addition to
Jardetzky and Lamb, other authors on the
paper are postdoctoral fellow
Hsien-Sheng Yin (first author) of the
Howard Hughes Medical Institute and
Northwestern, and research associate
Xiaolin Wen and research assistant
professor Reay G. Paterson, from
Northwestern.
Megan Fellman
fellman@northwestern.edu
Northwestern University
www.northwestern.edu
This article can be viewed at the
Medical News Today website:
http://www.medicalnewstoday.com/medicalnews.php?newsid=35808
|
|
|
|