Structure of viral harpoon protein reveals how viruses enter cells

January 05, 2006 infosys

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A team of Northwestern University researchers has solved the structure of a molecule that controls the ability of viruses of the paramyxovirus family, including the viruses that cause measles, mumps, and many human respiratory diseases, to fuse with and infect human cells. Determining the structure of this molecule and its role in the viral fusion mechanism may aid the development of drugs and vaccines that target these types of viruses, say the scientists, whose work was funded by the National Institute of General Medical Sciences (NIGMS) and the National Institute of Allergy and Infectious Diseases (NIAID), both parts of the National Institutes of Health (NIH).

Viruses reproduce only within living cells. They attach to the plasma membrane of the host cell and release their nucleic acid into the cytoplasm of the cell. The capsid may remain outside the cell, or it may be digested by the host cell within the cytoplasm. In the host cytoplasm, the DNA or RNA of the viral genome encodes the proteins that act as enzymes for the synthesis of new viruses. The enzymes use amino acids in the cell for protein synthesis and nucleotides from the host DNA for nucleic acid synthesis. The viruses obtain cellular ATP and use cellular ribosomes for additional viral synthesis. After some minutes or hours, the new viral capsids and genomes combine to form new viruses.

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Knowledge about viruses has also aided the development of DNA technology. Viruses are fragments of nucleic acid surrounded by a protein coat. In some cases, viruses attack cells and replicate within the cells, thereby destroying them. In other cases, the viruses enter cells, and their nucleic acid joins with the nucleic acid in the cell nucleus. By attaching DNA to viruses, scientists use viruses to transport foreign DNA into cells and to connect it with the nucleic acid of the cells.

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As described in the latest issue of the journal Nature, this large protein, called F, studs the surfaces of certain RNA viruses that are encased in a membrane envelope. As soon as such a virus comes in contact with a cell it can infect, the F protein changes shape and extends like a harpoon into the outer membrane of that cell. Then the protein undergoes a conformational (shape) change and collapses upon itself, pulling the virus against the host cell and fusing the viral membrane with the target cell's membrane. The fusion unleashes the viral RNA into the cell, which then hijacks the cell's machinery to make and spread more virus.

Once formed, the viruses may escape the host cell when the host cell disintegrates. Alternately, the new viruses may force their way through the plasma membrane of the cell and assume a portion of the plasma membrane as a viral envelope. In either process, the cell is often destroyed and hundreds of new viruses are produced.

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"Because of F protein's central role in viral infection, solving the structure of this critical protein is truly a great advance in biomedical science," says Elias A. Zerhouni, M.D., NIH director. intel
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Even though the basic concept of viral fusion has been understood for some time, the complete conformations of the structures of the before- and after-fusion forms of the F protein had eluded scientists until the recent work of the Northwestern team, which was led by Theodore Jardetzky, Ph.D., and Robert Lamb, Ph.D., Sc.D. What has allowed Drs. Jardetzky, Lamb and their colleagues to understand these new mechanistic details is the fact that they determined the structure of the pre-fusion form of the protein-before the protein has harpooned a cell. averatec
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"Such structural details offer valuable insights into how viruses infect cells and underscore the contributions of basic science to improving human health," says Jeremy M. Berg, Ph.D., NIGMS director. dual xeon
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"The findings may point the way to new medical interventions, such as drugs or vaccines, for infections caused by enveloped RNA viruses," adds Anthony S. Fauci, M.D., NIAID director. seagate
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About the Protein and How its Structure was Solved computer hardware
The F protein that the research team solved is from a parainfluenza virus. Not to be confused with the similar yet distinct Orthomyxoviridae viruses that cause influenza, parainfluenza viruses belong to a family of viruses known as paramyxoviruses. Besides human parainfluenza virus, this family includes human and animal pathogens such as mumps virus, measles virus, human respiratory syncytial virus (a common cause of pneumonia in children) and the animal pathogens canine distemper virus and rinderpest virus. In addition to these paramyxoviruses, there are several other enveloped RNA viruses that use a similar fusion mechanism to enter human cells, including those that cause influenza, AIDS and SARS. printers
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Solving the structure of this protein proved difficult, the scientists say, because F is an unusual protein that exists in two different forms, including the metastable shape that it adopts before it harpoons a cell and collapses into its stable post-fusion conformation. Solving the metastable structure was difficult because the anchoring of F to the virus surface (or membrane) is important for holding F in this active state. The protein's structure could not be solved unless it was in the membrane, but solving a protein structure like this required that it be separated from the membrane. mainframe
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To accomplish this, the scientists utilized a bit of molecular trickery. They replaced the part of the protein that is embedded in the viral membrane with an engineered piece of protein that acts as a substitute. Thus, the F protein was stabilized in its pre-fusion form and could be crystallized. Then, using the Advanced Photon Source at the U.S. Department of Energy's Argonne National Laboratory, the research team employed high intensity X-rays to obtain data from the crystals, which they then interpreted in order to reconstruct the structure of the F fusion protein-the culmination of several years' worth of research. computer repair
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Drs. Jardetzky, Lamb, and their colleagues also compared this structure to the structure of the protein in the transformed post-fusion form. This allowed them to observe how the protein undergoes a radical shape change upon harpooning a target cell. This turned out to be one of the most dramatic rearrangements of a protein ever observed. "[The fusion protein] breaks a lot of rules about protein folding," says Dr. Jardetzky, explaining that it does not adopt a single, stable conformation as one normally expects from a protein but rather exists in two very different conformations depending on whether it has harpooned a cell or not. "It's giving us new ideas about how flexible protein structures can be." network
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And by seeing these F structures in atomic detail, scientists will now be able to target for intervention similar proteins on the measles virus, mumps virus, human respiratory disease viruses, and others in ways that were not possible before. "What you learn about one paramyxovirus fusion protein applies to all the others," adds Dr. Lamb. desktops

NIH/National Institute of Allergy and Infectious Diseases