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The structure of NatA, an n-terminal acetyltransferase, is described in a paper published Aug. 4, 2013, in Nature Structural & Molecular Biology.
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A team of researchers from Philadelphia and Norway has determined the structure of an enzyme complex that modifies one end of most human proteins and is made at elevated levels in numerous forms of cancer. A study in Nature Structural & Molecular Biology, led by researchers at The Wistar Institute, depicts the structure and the means of action of a protein complex called NatA. Their findings, they believe, will allow them to create an inhibitor—a potential drug—that could knock out NatA in order to curb the growth of cancer cells.
"NatA appears essential for the growth of cells and their ability to divide, and we can see elevated production of this enzyme in many forms of cancer" said Ronen Marmorstein, Ph.D., senior author, Hilary Koprowski, M.D. Professor, and leader of The Wistar Institute Cancer Center's Gene Expression and Regulation program. "Obviously, this is a particularly appealing drug target and we are currently leveraging our recent understanding of how the protein works to develop small molecules that will bind to and inactivate NatA."
NatA is a member of a family of N-terminal acetyltransferase (NAT) enzymes (or enzyme complexes) that modify proteins in order to control their behavior—for example by turning proteins on, telling proteins where to move, and tagging proteins or the cell for destruction.
According to Marmorstein, NatA works with an amazing specificity for a particular sequence of amino acids—the individual building blocks of proteins—and unraveling the roots of that specificity has proven an alluring puzzle for scientists.
The Marmorstein laboratory has proven expertise in the study of acetylation enzymes, proteins that modify other molecules in the cell with an acetyl group "tag." In the cellular world, structure dictates function, and acetylation is a universal process for controlling protein behavior and gene expression in living organisms.
"Modifying protein structures is one way that our cells control how proteins function," Marmorstein explained, "and enzymes in the NAT family modify nearly 85 percent of human proteins, and 50 percent of these are modified by NatA."
According to Marmorstein, NatA operates in a complex of two proteins, an enzymatic subunit and an auxiliary partner. When they developed the structure of NatA—by bombarding a crystallized sample of the enzyme with powerful X-rays—they found how the auxiliary partner protein is crucial for turning the enzymatic subunit on.
Binding to an auxiliary protein causes a structural change in the enzymatic subunit that properly configures the active site of the protein—the region of the protein where the chemical reaction occurs—essentially acting as a switch that activates the enzyme.
"When it binds to its auxiliary protein, the enzymatic subunit of NatA actually changes shape, reconfiguring the structure to allow it to properly grab its target protein N-terminal sequence for acetylation," Marmorstein said.
Importantly, others have found that NatA function is required for the proliferation of cancer cells. Marmorstein says, understanding the structure of NatA has allowed his team to better understand how to inactivate the protein in cancer cells. The structure has yielded targets for small molecules that will act as inhibitors, essentially stopping the protein by gumming up its structure.
INFORMATION:
The lead author of this study is Glen Liszczak, Ph.D., a graduate student working at the Wistar Institute from the University of Pennsylvania Department of Chemistry. Other co-authors of this study include, Jacob M. Goldberg, and E. James Petersson, Ph.D., from the University of Pennsylvania's Department of Chemistry; and Hårvard Foyn, Ph.D., and Thomas Arnesen, Ph.D., from the University of Bergen, Norway.
Funding for this project was through the National Institutes of Health grants GM060293 and GM071339. The Arnesen laboratory's efforts were supported by the Research Council of Norway and the Norwegian Cancer Society.
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Cambridge-- As anyone who has traveled with young children knows, maintaining focus on distant goals can be a challenge. A new study from MIT suggests how the brain achieves this task, and indicates that the neurotransmitter dopamine may signal the value of long-term rewards. The findings may also explain why patients with Parkinson's disease — in which dopamine signaling is impaired — often have difficulty in sustaining motivation to finish tasks.
The work is described this week in the journal Nature.
Previous studies have linked dopamine to rewards, and have shown ...
Chemically modified inhibitors of the COX-2 enzyme relieve anxiety behaviors in mice by activating natural "endocannabinoids" without gastrointestinal side effects, Vanderbilt University scientists will report next week.
Endocannabinoids are natural signaling molecules that activate cannabinoid receptors in the brain, the same receptors turned on by the active ingredient in marijuana.
These receptors are also found in the gastrointestinal system and elsewhere in the body, and there is evidence that they play a role in wide range of physiological and pathological processes, ...
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In a study appearing online August 4 in Nature, NYU Langone Medical Center researchers decipher how oxytocin, acting as a neurohormone in the brain, not only reduces background noise, but more importantly, ...
Scientists at the University of East Anglia have shown that sequencing the DNA of crushed up creepy crawlies can accelerate the monitoring and cataloguing of biodiversity around the world.
Research published today in the journal Ecology Letters shows that a process known as 'metabarcoding' is much faster than and just as reliable as standard biodiversity datasets assembled with traditional labour-intensive methods.
The breakthrough means that changing environments and endangered species can be monitored more easily than ever before. It could help researchers find endangered ...
HONOLULU – Vulnerability to alcohol and drug abuse may begin in the womb and be linked to how much fatty and sugary foods a mother eats during pregnancy, according to findings from animal lab experiments presented at APA's 121st Annual Convention.
"The majority of women in the U.S. at child-bearing age are overweight, and this is most likely due to overeating the tasty, high-fat, high-sugar foods you find everywhere in our society. The rise in prenatal and childhood obesity and the rise in number of youths abusing alcohol and drugs merits looking into all the possible ...
HONOLULU – Multiracial people may be misidentified more often as being white than black and may value being accurately identified more so than single-race individuals, according to research presented at APA's 121st Annual Convention.
"Today, the distinctions among white, black, Latino and Asian people are becoming blurred by the increasing frequency and prominence of multiracial people," said Jacqueline M. Chen, PhD, of the University of California, Davis. "Still, average Americans have difficulty identifying multiracial people who don't conform to the traditional single-race ...
A person playing a first-person shooter video game like Halo or Unreal Tournament must make decisions quickly. That fast-paced decision-making, it turns out, boosts the player's visual skills but comes at a cost, according to new research: reducing the person's ability to inhibit impulsive behavior. This reduction in what is called "proactive executive control" appears to be yet another way that violent video games can increase aggressive behavior.
"We believe that any game that requires the same type of rapid responding as in most first-person shooters may produce similar ...
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The SLIPS coating makes glass so slippery that droplets of liquids slip off quickly even at a shallow angle. Here, from top to bottom, a droplet of octane, an ingredient...
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August 2, 2013 – A new transparent, bioinspired coating makes ordinary glass tough, self-cleaning and incredibly slippery, a team from the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard School of Engineering and Applied Sciences ...
Sacramento, CA (August 2, 2013) – In a new observational study published in the Journal of Food Science, researchers looked at the association of grape consumption, in the non-alcoholic forms most commonly consumed – fresh grapes, raisins and 100% grape juice – with the diet quality of a recent, nationally representative sample of U.S. children and adults. Their findings suggest that, among adults and children, consumption of grapes and grape products is associated with healthier dietary patterns and improved nutrient intakes.
Researchers analyzed the diets of more than ...
By differentiating monkey stem cells into liver cells and inducing successful infection, researchers from the Icahn School of Medicine at Mount Sinai have shown for the first time that the hepatitis C virus (HCV) can replicate in monkeys, according to research published in the journal Gastroenterology. The new findings may lead to the first new animal model and provide new avenues for developing treatments and vaccines for this disease, which impacts more than three million people in the United States.
Scientists have tried for decades to develop animal models to study ...
