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Viruses protect selves with protein armor

Pitt researchers find bacterial viruses protect themselves with finely knit protein strands

Monday, August 10, 1998

By Byron Spice, Science Editor, Post-Gazette

The chain mail worn by European knights to protect against spears and swords was the cutting edge of 11th century technology. But unbeknownst to the guildsmen who forged the armored fabric, the idea that interlocking rings can make a strong material was nothing new to nature.

Only recently, in fact, have researchers at the University of Pittsburgh discovered that bacterial viruses use chain mail -- albeit made of protein instead of iron -- to strengthen their outer shells.

The hundreds of polypeptide strands that make up the viral shell, or capsid, are held together not only by chemical bonds, but also by looping around each other. The result, said Roger Hendricks, a Pitt professor of biological sciences, is an unusually strong capsid that is impervious to most environmental insults.

It's the first time that anyone has suggested that proteins might use this combination of chemical and physical bonds. Because no one has thought to look for this structure, it's anyone's guess whether it's common throughout the biosphere or largely restricted to these bacterial viruses, called bacteriophages.

"Chain mail itself is a new property," said Robert Duda, a senior research associate at the Pittsburgh Bacteriophage Institute who first conceived the idea. It could be used to form flat surfaces or rolled to make thin, strong tubes. "We don't know where it's going to be found," said Duda, whose report on protein chain mail appeared last month in the journal Cell.

The chances that such a structure would evolve in bacteriophages and then be discarded in other species seem small to John Johnson, a professor of molecular biology at the Scripps Research Institute in La Jolla, Calif.

"Once you find these things one place, they tend to show up other places," he added.

If researchers ever master the art of getting proteins to fold and assemble themselves into tissues, protein chain mail might prove a helpful trick in building engineered biomaterials, such as arteries, skin grafts or replacement organs, said Peter Prevelige Jr. of the University of Alabama at Birmingham.

"This shows, once again, that nature is light years ahead of us," he added.

The discovery of protein chain mail, like so many scientific discoveries, was something of a fluke and probably wouldn't have occurred if Hendricks and Duda weren't such finicky experimenters.

They weren't looking for protein chain mail, but indulging their preoccupation with bacteriophages, one of the most diverse and ancient populations in the biosphere. They are so prolific, Hendricks said, that if each bacteriophage, or phage, was the size of a cockroach, the world's phages would form a layer 30,000 miles thick around the globe.

Like other viruses, phages are parasites that inject their DNA into cells and use the cellular machinery of their hosts to multiply. Phages don't infect humans or other animals, but only attack bacteria.

By moving around so much genetic material, phages play an important role in the evolution of bacteria. It was a phage, for instance, that added a toxin gene to the common intestinal bacteria called E. coli, creating the virulent strain known as 0157.H7 that has been implicated in deaths involving undercooked hamburger.

When phages were discovered in 1917, some scientists suggested they might be used to fight bacterial infections. That interest largely evaporated when highly effective chemical antibiotics were discovered. With the rise of antibiotic-resistant strains of bacteria, however, clinical interest in phages may someday be renewed.

Biologists have used phages as tools for genetic engineering, but also have studied them to better understand genetic mechanisms and other principles.

"They're simple enough that we can sustain the fantasy that we can someday understand everything about them," Duda said.

Viruses that infect animals must shed their spherical viral coat to release their DNA into cells. But phages look like tiny lunar landing modules -- an angular capsid, or head, that contains the DNA and sits atop a long tail. The tail attaches to a cell and the phage then injects its DNA into the cell, working much like a hypodermic needle.

Hendricks and Duda had been curious about why each type of phage grew tails of the same length. After studying a well-known phage called bacteriophage lambda, they found what they thought was a protein that acted like a measuring tape.

Looking to test their idea, Hendricks came across a phage called HK97. Isolated by Hong Kong researchers from pig dung, HK97 wasn't particularly distinguished, but it looked an awful lot like bacteriophage lambda, except with a longer tail. When he and Duda tested a sample, they found the measuring tape hypothesis held true.

But then the Pitt researchers performed a routine analysis of the capsid that produced a curious result. First they boiled the capsids in a detergent solution. This causes the shell's proteins, which normally look like clumps of folded spaghetti, to break apart from each other, become electrically charged and unfold.

They then performed what is called a gel electrophoresis. The digested proteins are placed on a thin gel, to which an electrical field is applied. The electrical field pulls the smallest, lightest bits of protein quickly across the gel. Larger pieces move more slowly. The bits line up in a way that allows scientists to analyze how big the various components are.

The capsid vaguely resembles a soccer ball, consisting mainly of rings of six proteins, with rings of five proteins at the corners to help shape the capsid into a rough sphere. So Duda and Hendricks expected to see lots of five- and six-protein bits in the electrophoresis gel.

What surprised them was that most of the material hardly entered the gel. The pieces were too big.

Most researchers would simply have shrugged and moved on. But Hendricks and Duda kept looking to explain the weird results.

What could cause such big lumps? They knew the proteins in each ring were chemically bonded together, but was there some additional chemical bond that would hold the rings to each other? If so, they couldn't find it.

Then Duda began wondering if some of the rings didn't unfold into straight strands, but remained circular. Would that make them move faster or slower through the gel? While he pondered that question, however, a light bulb went on inside his head.

What if the rings were interlinked, like chain mail? "In a sense, this isn't a gigantic leap," Duda admitted, but it was an explanation that seemed to fit perfectly with the results they saw.

Scientists had always envisioned proteins connecting together almost like Lego blocks, Hendricks said. But the construction process now appears more like a ballet.

He suggests thinking about it in terms of groups of people standing in separate circles, holding hands. But before they join hands, a person in one ring first reaches over the arm of a person in an adjacent ring. The people are bound in each ring by their hands -- the equivalent of chemical bonds -- but also are bound physically to adjoining rings.

When he first heard the idea, Johnson, an authority on viral structure at Scripps, found it difficult to believe. "I could have looked at that data for a long time and never come up with that explanation," he said. But when he studied their data, he and other colleagues could find no reason to disagree.

"I can't see any other reasonable explanation," agreed Alabama's Prevelige. "I think the data they have is as convincing as can be."

To date, no one has actually seen these interlinked proteins. Two years ago, however, Johnson began to develop a map of a capsid using a technique called X-ray crystallography. It will take another year to complete the map, identifying the location of each atom in the capsid. But all the detail that he has seen thus far is consistent with the idea of protein chain mail.

Sherwood Casjens, a professor of oncological science at the University of Utah Medical School, said it seems likely that protein chain mail is present in other organisms, but might be difficult to ferret out. Chain mail would be easier to see in a phage, he explained, because a phage has a very regular structure -- "That's why we study it."

But sometimes something can't be found simply because no one has bothered to look, Hendricks said. "If there are other structures like this out there, people will start finding them now."

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