Featured Research

from universities, journals, and other organizations

Structure Of Viral Harpoon Protein Reveals How Viruses Enter Cells

Date:
January 6, 2006
Source:
NIH/National Institute of Allergy and Infectious Diseases
Summary:
A team of 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 NIGMS and NIAID, both parts of NIH.

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).

Related Articles


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.

"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.

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.

"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.

"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.

About the Protein and How its Structure was Solved
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.

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.

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.

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."

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.

###

NIGMS (http://www.nigms.nih.gov), a component of the National Institutes of Health, supports basic biomedical research that is the foundation for advances in disease diagnosis, treatment and prevention.

NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies.

Reference: H-S Yin et al. Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation. Nature DOI: 10.1038/nature04322 (2006).


Story Source:

The above story is based on materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Materials may be edited for content and length.


Cite This Page:

NIH/National Institute of Allergy and Infectious Diseases. "Structure Of Viral Harpoon Protein Reveals How Viruses Enter Cells." ScienceDaily. ScienceDaily, 6 January 2006. <www.sciencedaily.com/releases/2006/01/060105090228.htm>.
NIH/National Institute of Allergy and Infectious Diseases. (2006, January 6). Structure Of Viral Harpoon Protein Reveals How Viruses Enter Cells. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2006/01/060105090228.htm
NIH/National Institute of Allergy and Infectious Diseases. "Structure Of Viral Harpoon Protein Reveals How Viruses Enter Cells." ScienceDaily. www.sciencedaily.com/releases/2006/01/060105090228.htm (accessed November 26, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, November 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Pet Dogs to Be Used in Anti-Ageing Trial

Pet Dogs to Be Used in Anti-Ageing Trial

Reuters - Innovations Video Online (Nov. 26, 2014) Researchers in the United States are preparing to discover whether a drug commonly used in human organ transplants can extend the lifespan and health quality of pet dogs. Video provided by Reuters
Powered by NewsLook.com
Today's Prostheses Are More Capable Than Ever

Today's Prostheses Are More Capable Than Ever

Newsy (Nov. 26, 2014) Advances in prosthetics are making replacement body parts stronger and more lifelike than they’ve ever been. Video provided by Newsy
Powered by NewsLook.com
From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

Newsy (Nov. 25, 2014) The US FDA is announcing new calorie rules on Tuesday that will require everywhere from theaters to vending machines to include calorie counts. Video provided by Newsy
Powered by NewsLook.com
Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Newsy (Nov. 25, 2014) Need another reason to eat yogurt every day? Researchers now say it could reduce a person's risk of developing type 2 diabetes. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins