Tag: Proteins

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Surprising Role for Protein Involved in Cell Death

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C. elegans
Many of the key players in regulating apoptosis were discovered in C. elegans. This tiny roundworm has more than 19,000 genes, and a vast number of them are very similar to genes in other organisms, including people. Credit: Ewa M. Davison.

Our cells come equipped with a self-destruct mechanism that’s activated during apoptosis, a carefully controlled process by which the body rids itself of unneeded or potentially harmful cells. Scientists have long known that a protein called PSR-1 helps clean up the cellular remains. Now they’ve found that PSR-1 also can repair broken nerve fibers.

Ding Xue of the University of Colorado, Boulder, and others made the finding in the tiny roundworm C. elegans, which scientists have used to study apoptosis and identify many of the genes that regulate the process. While apoptotic cells sent “eat me” signals to PSR-1, injured nerve cells sent “save me” signals to the protein. These SOS signals helped reconnect the broken nerve fibers, called axons, that would otherwise degenerate after an injury.

Continue reading “Surprising Role for Protein Involved in Cell Death”
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Remotely and Noninvasively Controlling Genes and Cells in Living Animals

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Remote control car key.
Researchers are developing a system to remotely control genes or cells in living animals with radio wave technology similar to that used to operate remote control car keys. Credit: Stock image.

One of the items on biomedical researchers’ “to-do” list is devising noninvasive ways to control the activity of specific genes or cells in order to study what those genes or cells do and, ultimately, to treat a range of human diseases and disorders.

A team of scientists recently reported progress on a new, noninvasive system that could remotely and rapidly control biological targets in living animals. The system can be activated remotely using either low-frequency radio waves or a magnetic field. Similar radio wave technology operates automatic garage-door openers and remote control car keys and is used in medicine to control electronic pacemakers noninvasively. Magnetic fields are used to activate sensors in burglar alarm systems and to turn your laptop to hibernate mode when the cover is closed. Continue reading “Remotely and Noninvasively Controlling Genes and Cells in Living Animals”

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Untangling a Trending Topic

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It’s not every day that we log into Facebook and Twitter to see conversations about denaturing proteins and the possibility of reducing biotechnology costs, but that changed last week when a story about “unboiling” eggs became a trending topic.

Since NIGMS partially funded the research advance Exit icon that led to the media scramble, we asked our scientific expert Jean Chin to tell us more about it.

What’s the advance?

Gregory Weiss of the University of California, Irvine, and his collaborators have designed a device that basically unties proteins that have been tangled together. Continue reading “Untangling a Trending Topic”

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New Research Sheds Light on Drug-Induced Salivary Issues

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Open human mouth
Scientists have discovered a possible mechanism behind the bad taste and dry mouth caused by some drugs. Credit: Stock image.

The effects some medicines have on our salivary glands can at times extend beyond the fleeting flavor we experience upon ingesting them. Sometimes drugs cause a prolonged bad taste or dryness in the mouth, both of which can discourage people from taking medicines they need. Now, a research team led by Joanne Wang of the University of Washington has discovered a possible mechanism behind this phenomenon. Working primarily with mice and using a commonly prescribed antidiabetic drug known to impair taste, the scientists identified a protein in salivary gland cells that takes up the drug from the bloodstream and secretes it in saliva. Wang and her colleagues were also able to pinpoint a specific gene that, when removed, hindered this process. They hope their new insights will aid efforts to develop medicines that do not cause salivary issues.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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Restoring the Function of an Immune Receptor Involved in Crohn’s Disease

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Gut bacteria
Receptor proteins bind to bacterial cell wall fragments, initiating an immune response to remove bad gut bacteria. Credit: S. Melanie Lee, Caltech; Zbigniew Mikulski and Klaus Ley, La Jolla Institute for Allergy and Immunology.

Our bodies depend on a set of immune receptors to remove harmful bacteria and control the growth of helpful bacteria in our guts. Genetic changes that alter the function of the receptors can have an adverse effect and result in chronic inflammatory diseases like Crohn’s disease. Catherine Leimkuhler Grimes and Vishnu Mohanan of the University of Delaware researched a Crohn’s-associated immune receptor, NOD2, to figure out how it can lose the ability to respond properly to bacteria. In the process, they identified the involvement of a protective protein called HSP70. Increasing HSP70 levels in kidney, colon and white blood cells appeared to restore NOD2 function. This work represents a first step toward developing drugs to treat Crohn’s disease.

This work was funded in part by an Institutional Development Award (IDeA) Network of Biomedical Research Excellence (INBRE) grant.

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Intercepting Amyloid-Forming Proteins

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Structure of a protein involved in disease-associated amyloid fibrils.
A molecule targets the intermediary structure of a protein involved in disease-associated amyloid fibrils. Credit: University of Washington.

Alzheimer’s disease, type 2 diabetes and many other illnesses are linked to the buildup of proteins whose structures have changed into shapes that enable the formation of cell-entangling threads called amyloid fibrils. About 10 years ago, researchers led by Valerie Daggett of the University of Washington used computer simulations to suggest that such proteins, on their way to creating fibrils, form an intermediary structure called an alpha sheet that’s even more toxic to cells than fibrils. Now Daggett’s team has experimentally investigated this possibility. The scientists made alpha sheet molecules expected to bind to amyloid-forming proteins in the computationally predicted intermediate state. When they tested the molecules on two amyloid disease-related proteins, they observed a substantial reduction in fibril formation. The work is still very preliminary, but it highlights a potential new avenue for treating a range of amyloid-related diseases.

This work also was funded by NIH’s National Institute of Allergy and Infectious Diseases.

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Monster Mash: Protein Folding Gone Wrong Article from Inside Life Science

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A Data Bank Built for Discovery

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Dynein, a motor protein. Credit: David S. Goodsell, The Scripps Research Institute and the RCSB PDB.
The PDB archive holds structural data for dynein, a motor protein, and more than 100,000 other molecules. Credit: David S. Goodsell, The Scripps Research Institute and the RCSB PDB. Click for larger image

Meet dynein, the August Molecule of the Month presented by the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). This motor protein travels along the cables of our cellular skeleton, delivering cargo throughout the cell. The structure of dynein’s stalk enables it to bind to regular grooves along its path.

Dynein’s shape is just one of more than 100,000 structures that scientists have deposited in the PDB archive, a freely available digital repository. Because understanding a protein’s shape helps researchers better understand its function, the structural information in the PDB can lead to additional scientific advancements. For example, scientists use the structure of HIV protease, a protein that helps the virus replicate in the body, to develop drugs that fit snugly into the protein’s center, shutting it down. And they use the shape of RNA polymerase to learn how this protein fits together with smaller ones to read our genetic code.

The PDB has doubled in size over the last 6 years. As the collection continues to grow, so does our potential for drug discovery and our understanding of basic life processes.

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Molecule of the Month Archive from RCSB PDB

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How Heat-Loving Organisms Are Helping Advance Medicine

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Hot spring. Credit: Stock image.
Icelandic hot springs are the natural habitat of Rhodothermus marinus, one of many species of thermophiles that the Gennis Lab studies to better understand membrane proteins. Credit: Stock image.

As the temperature climbs, most humans look for ways to cool down fast. But for some species of microorganisms, a midsummer heat wave isn’t nearly hot enough. These heat lovers, known as thermophiles, thrive at temperatures of 113°F or more. They’re often found in hot springs, geysers and even home water heaters.

Like humans and other organisms, thermophiles rely on proteins to maintain normal cell function. While our protein molecules break down under intense heat, a thermophile’s proteins actually work more efficiently. They also tend to be more stable at room temperature than our own. An NIH-funded research team is taking advantage of this property of thermophiles to better understand a group of human proteins commonly targeted by today’s medicines.

Read more about the team’s thermophile research in this Inside Life Science article.

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A Drug-Making Enzyme in Motion

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Mutated enzyme, LovD9. Credit: Silvia Osuna and Gonzalo Jiménez-Osés, University of California, Los Angeles.
The movement of this mutated enzyme, LovD9, facilitates rapid production of the cholesterol reducing-drug simvastatin. Credit: Silvia Osuna and Gonzalo Jiménez-Osés, University of California, Los Angeles.

LovD9, a mutated version of an enzyme extracted from mold growing in soil, produces the cholesterol-reducing drug simvastatin 1,000 times faster than its natural predecessor. But scientists didn’t understand why because the enzyme’s mutations are far from the active site, where the drug is actually made. Now they do.

Yi Tang of the University of California, Los Angeles (UCLA), in partnership with the pharmaceutical company Codexis, generated LovD9 by repeatedly inducing random mutations, each time selecting the mutated versions of the enzyme with the most promise for industrial simvastatin production.

Then, the team collaborated with UCLA colleagues Kendall Houk and Todd Yeates to unlock the secret of the enzyme’s speed. Using ANTON, a special-purpose supercomputer at the Pittsburgh Supercomputing Center, they simulated how different parts of the enzyme rotate and twist when synthesizing the drug. The scientists discovered that as LovD9 moves, it forms shapes that facilitate simvastatin production more often than the natural enzyme does.

With their better understanding of how mutations far from an active site may affect an enzyme’s motion, the researchers hope to one day directly engineer enzymes with precise mutations that enhance drug production.

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Houk Exit icon, Tang Exit icon and Yeates Exit icon Labs

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New Compound Improves Insulin Levels in Preliminary Studies

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compound
A new compound (chemical structure shown here) blocks the activity of an enzyme involved in glucose regulation.

The discovery of a compound that slows the natural degradation of insulin in mice opens up a new area of investigation in the search for drugs to treat diabetes. The research team, which included David Liu Exit icon and Alan Saghatelian Exit icon of Harvard University, Markus Seeliger of Stony Brook University School of Medicine, and Wei-Jen Tang Exit icon of the University of Chicago focused on insulin-degrading enzyme, or IDE. Using a method called DNA-templated synthesis, the scientists made 14,000 small molecules and found one that bound to the enzyme, suggesting it might modulate the enzyme’s activity. Work in test tubes and in animal models confirmed this—and showed that blocking IDE activity improved insulin levels and glucose tolerance. The researchers also learned that the enzyme is misnamed: In addition to insulin, it degrades two other hormones involved in glucose regulation.

NIGMS’ Peter Preusch says, “This is a very interesting fusion of chemical methods and biology that has uncovered new basic science findings about insulin processing with potential clinical impact.”

This work also was funded by NIH’s National Cancer Institute and the Office of the Director.

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Chemistry of Health Booklet