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Bizarre New Protein Blocks A Real-Life Terminator

Date:
September 19, 2001
Source:
Stanford University
Summary:
Researchers have discovered a bacterial protein that could turn out to be an evolutionary ancestor of disease-fighting antibodies in humans.

Researchers have discovered a bacterial protein that could turn out to be an evolutionary ancestor of disease-fighting antibodies in humans.

In a study published in the Sept. 14 issue of the journal Science, Stanford Professor Emeritus Charles Yanofsky and postdoctoral fellow Angela Valbuzzi describe how they were the first to isolate a protein they call anti-TRAP (AT) from the bacterium Bacillus subtilis.

``This protein has unique binding properties,`` says Yanofsky, the Morris Herzstein Professor of Biology, Emeritus. ``We struggled for some time to come up with an appropriate name for it, and AT was the simplest.``

Although its name is simple, the newly discovered protein participates in a very complex metabolic network presently known only to exist in several species of Bacillus bacteria. Yanofsky and Valbuzzi determined that AT helps bacilli regulate the production of tryptophan - one of 20 amino acids that are the building blocks of most proteins in all living organisms, including people.

A protein is essentially a large chain of amino acids strung together inside a tiny cellular factory known as the ribosome. The human body uses the aminoacid tryptophan to make thousands of proteins and other important molecules,including niacin, or Vitamin B3.

People must get their tryptophan from food - unlike bacteria, which can manufacture their own supplies internally. Infants require large amounts of tryptophan for normal development, and diets poor in tryptophan can result in pellagra - a disease of the skin and central nervous system caused by niacin deficiency.

The terminator

In the 1970s, Yanofsky and his colleagues discovered a previously unknown mechanism for regulating tryptophan production in Escherichia coli - a common bacterium that lives in the intestines of humans and other vertebrates.

Their discovery focused on a molecule known as messenger RNA (mRNA), which carries the DNA-coded information for specific proteins to a component of the cell called the ribosome, where proteins are synthesized.

Using mRNA as a template, the ribosome instructs another class of molecules, called transfer RNAs (tRNAs), to bring in specific amino acids - such as tryptophan - and line them up in the exact sequence dictated by the mRNA. The result is the production of a protein chain consisting of a unique sequence of dozens of amino acids, which the ribosome then sets free for use inside the bacterium.

Yanofsky`s lab had previously determined that E. coli has the ability to start and stop the production of tryptophan depending on how much is present in the cell. They determined that a regulatory mechanism controls tryptophan production in E. coli by sensing whether there is a sufficient amount of tRNA loaded with tryptophan for the bacterium to carry out protein synthesis.

When tryptophan-loaded tRNA is abundant, a special hairpin loop - called a terminator - forms in the mRNA molecule, which causes premature termination of mRNA synthesis. However, when the tryptophan concentration is low, tryptophan-free tRNA blocks formation of the terminator, thereby allowing synthesis of the complete mRNA that encodes the tryptophan-synthesizing enzymes.

Bizarre Bacillus

In 1992, Yanofsky`s lab discovered that bacilli have an even stranger mechanism for regulating tryptophan formation. Like E. coli, bacilli use a hairpin-shaped terminator system to control tryptophan production. However, unlike E. coli, , or any other organism, bacilli regulate tryptophan formation with the help of a donut-shaped protein Yanofsky named TRAP - the Tryptophan-activated trp RNA-binding Attenuation Protein.

Some of Yanofsky`s previous co-workers, collaborating with British scientists, showed that in bacilli, the tryptophan-specific mRNA actually wraps itself around the TRAP molecule like a snow-chain wrapped around a tire.

``When tryptophan concentrations are high, tryptophan molecules attach themselves to the binding sites on TRAP, activating TRAP and allowing it to bind to mRNA, which causes the mRNA-terminator to form. This essentially turns off the genes needed to produce tryptophan,`` notes Valbuzzi, lead author of the Sept. 14 Science study.

``Conversely, when tryptophan levels are low, there aren`t enough molecules of tryptophan to bind to TRAP, therefore TRAP cannot bind to RNA. The mRNA antiterminator then forms, allowing mRNA synthesis to proceed to completion and tryptophan synthesis to begin,`` she adds.

Anti-TRAP

In their Sept. 14 study, Yanofsky and Valbuzzi go one step further. They determined that, in addition to sensing the amount of tryptophan present B. subtilis also has a means of detecting the concentration of tryptophan-specific transfer RNA. They discovered that if the amount of tryptophan-laden tRNA is low, a special set of genes in B. subtilis will begin producing the previously unknown protein AT (anti-TRAP).

Molecules of AT then latch onto TRAP`s RNA binding sites, thus preventing TRAP from binding to mRNA. As a result, a loop forms along the mRNA molecule, allowing mRNA synthesis to continue, which then directs the synthesis of the proteins that produce tryptophan.

``There still are many unknowns about the AT protein,`` says Yanofsky. ``What is its exact shape, and exactly where does it bind to the TRAP molecule? Furthermore, several AT molecules must be required to block TRAP`s RNA binding sites. Our current guess is between four and six. What is particularly interesting about AT is that it only binds to tryptophan-activated TRAP.``

Evolution

Why did B. subtilis> evolve such an elaborate and energetically costly mechanism for regulating tryptophan synthesis?

``It takes seven catalytic steps to synthesize tryptophan, making it one of the most expensive amino acids for an organism to produce, requiring large amounts of energy and carbon,`` Yanofsky explains. ``Therefore, having an efficient means of regulating the production of tryptophan is important.``

He points out that B. subtilis lives in the soil, whereas E. coli resides in several environments, including the guts of animals. For both organisms there probably are times when tryptophan is rare and other times when it is abundant. Evolution apparently provided efficient regulatory mechanisms for these organisms to cope with the need to regulate tryptophan formation.

Yanofsky speculates that the bacterial strategy of using the AT protein is comparable to the use of antibodies - special proteins in people and other vertebrates that bind to and fight off invading molecules and pathogens. He and his colleagues wonder whether it will be possible to engineer mutant forms of AT that can target disease-causing antigens in people.

``This protein appears to have a really bizarre mechanism of action,`` he concludes. ``It is a completely different strategy than the one used by E. coli and other bacteria.``


Story Source:

The above story is based on materials provided by Stanford University. Note: Materials may be edited for content and length.


Cite This Page:

Stanford University. "Bizarre New Protein Blocks A Real-Life Terminator." ScienceDaily. ScienceDaily, 19 September 2001. <www.sciencedaily.com/releases/2001/09/010919072814.htm>.
Stanford University. (2001, September 19). Bizarre New Protein Blocks A Real-Life Terminator. ScienceDaily. Retrieved September 3, 2014 from www.sciencedaily.com/releases/2001/09/010919072814.htm
Stanford University. "Bizarre New Protein Blocks A Real-Life Terminator." ScienceDaily. www.sciencedaily.com/releases/2001/09/010919072814.htm (accessed September 3, 2014).

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