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Scientists identify molecular structure of key viral protein

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 prot ein 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.


Source:Northwestern University

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