How Protein Component That Enables Cell Replication Gets Ferried To Chromosome Tips

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Main Category: Genetics
Also Included In: Cancer / Oncology
Article Date: 04 Aug 2012 - 0:00 PDT Current ratings for:
How Protein Component That Enables Cell Replication Gets Ferried To Chromosome Tips

Stem cells are special. Nestled in muscle and skin, organ and bone, they bide their time over years or decades until called to replace damaged or lost tissue. One secret to their longevity is an enzyme called telomerase, which stills the relentless ticking of the molecular clock that limits the life span of other cells.

This cellular fountain of youth prevents the progressive shortening of the tips of our chromosomes that occurs with each cell division. But the presence of telomerase can be a double-edged sword: The same activity that ensures long life for stem cells can also keep a cancer cell dividing long after its aging neighbors have thrown in the towel. Conversely, a malfunction can prevent stem cells from doing their job and lead to devastating diseases.

Now, for the first time, researchers at the Stanford University School of Medicine have identified how telomerase is recruited to chromosome ends - and figured out a way to block it.

"If telomerase is unable to maintain the ends of the chromosomes, cells will stop multiplying," said professor of medicine Steven Artandi, MD, PhD. "This would be advantageous in cancer cells, but in normal stem cells it can cause severe dysfunction and lead to diseases such as pulmonary fibrosis, aplastic anemia and a genetic condition called dyskeratosis congenita. We want to understand how telomerase works, and to develop therapies for cancer and these other diseases."

Artandi is the senior author of the research, which was published in Cell. He is also a member of the Stanford Cancer Institute. Graduate student Franklin Zhong is the first author of the study.

Telomerase is normally expressed in adult stem cells and immune cells, as well as in cells of the developing embryo. In these cells, the enzyme caps off the ends of newly replicated chromosomes, allowing unfettered cell division. Without telomerase, cells stop dividing or die when the ends - called telomeres - fall below a minimum length. Unfortunately, the enzyme is also active in nearly all cancer cells.

Earlier research in Artandi's lab identified a protein called TCAB1 that brings the telomerase complex (actually a large clump of many proteins) to a processing area in the cell's nucleus called a Cajal body. But no one knew how the complex was then ferried to the ends of telomeres, and research was stymied by the complex's large size, multiple components and relative scarcity.

"This problem has been really intractable," said Artandi. "The enzyme is extremely hard to study. But we've now found that telomerase is recruited to the telomeres through an interaction with a protein called TPP1 that coats the ends of chromosomes." What's more, the researchers have identified the exact region of TPP1 to which telomerase binds - a section called an OB-fold.

"When we mutated this site in TPP1," said Artandi, "we blocked the interaction between the two proteins and prevented telomerase from going to the telomeres. And when we interfered with this interaction in human cancer cells, the telomeres began to shorten." The researchers are now assessing whether the life span of the cancer cells, and their ability to divide unchecked, will also be affected by the treatment.

To confirm their finding, Artandi and his colleagues used cells from patients with pulmonary fibrosis - a debilitating scarring or thickening of lung tissue associated with telomerase mutations. The disease had been troubling to researchers and clinicians, however, because the patients' mutated telomerase seemed to be fully active when tested in the laboratory. Zhong and Artandi found that the disease-associated mutations occurred in the portion of telomerase that interacted with TPP1, and interfered with their binding. As a result the enzyme, although active, couldn't get to where it was needed.

"It was impossible to even begin to understand this mechanism before we knew how these two molecules interact," said Artandi. "But now that we're getting a handle on this, we can begin to think about developing inhibitors - maybe in the form of peptides or small molecules - that can mimic this disruption. This could be very valuable in cancer therapies."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject. In addition to Zhong and Artandi, other Stanford researchers involved in the work include postdoctoral scholars Luis Batista, PhD, and Adam Freund, PhD; graduate student Matthew Pech; and former graduate student Andrew Venteicher, PhD.
The research was supported by Singapore's Agency for Science, Technology and Research, the California Institute for Regenerative Medicine, the National Science Foundation, the Leukemia and Lymphoma Society, the Glenn Foundation for Medical Research and the National Institutes of Health.
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Communication Via Tiny Protein Triggers Defensive Response In Plants

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Water - Air Quality / Agriculture;  Public Health
Article Date: 13 Dec 2011 - 3:00 PST

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Scientists have discovered a new signal that helps invading bacteria communicate but also helps targeted rice plants coordinate defensive attacks on the disease-causing invaders, a finding that could lead to new methods of combatting infection not just in plants, but in humans.

Findings from the study, conducted by a team of researchers led by a University of California, Davis, scientist, were reported in the journal /i>PLoS ONE and in the journal Discovery Medicine.

"Just as invading armies often use coded messages to coordinate attacks on their targets, so single-celled bacteria use biological signals to communicate when they attack plants and animals," said Pamela Ronald, a UC Davis professor of plant pathology and the lead researcher on the study. "Scientists have known this for 20 years, however results from our study reveal a type of bacterial signal that has never been described before."

UC Davis has a long history of tackling agricultural and environmental challenges related to rice production in the United States and around the world. Today, campus researchers are using molecular biology to better understand how to improve the hardiness and yield of this grain, which is a staple food for more than half of the world's population and an important model for plant research.

Up until now, scientists thought that two major groups of bacteria used two distinctly different types of communication codes, Ronald said. However Ax21, the small protein examined in this study, doesn't fit into either of those previously identified communication codes.

Ax21 is made inside the bacterial cell and processed to generate a shorter signal that is secreted outside the bacterium. This signal tips off other bacteria to assemble themselves into elaborate protective bunkers, called biofilms, which make the bacteria resistant to drying out and antibiotic treatment.

"Additionally, Ax21 triggers a change in the expression of nearly 500 bacterial genes, transforming the bacteria from fairly benign organisms into fierce invaders," Ronald said.

"In essence, through communication and communal living, the bacteria increase their chances of survival and proliferation," she said, noting that in rice, the bacteria multiply rapidly in the arteries that transport water, causing the plant to wither and die.

While most rice plants have little defense against the Ax21-mediated bacterial attack, some rice plants carry an immune receptor called XA21 that detects the Ax21 protein produced by the invading bacteria. XA21 belongs to a large class of immune receptors in plants and animals.

The importance of these receptors in immunity is reflected in the awarding of the 2011 Nobel Prize in physiology and medicine to researchers Bruce Beutler of The Scripps Research Institute in La Jolla and Jules Hoffman of the National Center of Scientific Research in Strasbourg, France, for their discoveries of similar receptors in animals.

The new study points out that the Ax21 signaling protein triggers the XA21 immune receptor to biologically alert the plant to launch a powerful defense response against the invading bacteria. The researchers also demonstrated that Ax21 is present in a human disease-causing bacterium that is known to infect hospital patients.

"This study demonstrates that bacteria communicate using private messages. However, plants can intercept these messages and gain a tactical advantage in the evolutionary battle," Ronald said. " It's a fascinating story."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our infectious diseases / bacteria / viruses section for the latest news on this subject. Ronald has posted an article about the study on her blog, "Tomorrow's Table," at http://scienceblogs.com/tomorrowstable/.
Researchers collaborating on the study are from UC Davis and Kyung Hee University, Korea.
Funding for the study was provided by the U.S. Department of Agriculture and the National Institutes of Health.
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Missing Link Between DNA And Protein Shape

Main Category: Genetics
Also Included In: IT / Internet / E-mail
Article Date: 09 Dec 2011 - 1:00 PST

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Fifty years after the pioneering discovery that a protein's three-dimensional structure is determined solely by the sequence of its amino acids, an international team of researchers has taken a major step toward fulfilling the tantalizing promise: predicting the structure of a protein from its DNA alone.

The team at Harvard Medical School (HMS), Politecnico di Torino / Human Genetics Foundation Torino (HuGeF) and Memorial Sloan-Kettering Cancer Center in New York (MSKCC) has reported substantial progress toward solving a classical problem of molecular biology: the computational protein folding problem.

The results were published in the journal PLoS ONE.

In molecular biology and biomedical engineering, knowing the shape of protein molecules is key to understanding how they perform the work of life, the mechanisms of disease and drug design. Normally the shape of protein molecules is determined by expensive and complicated experiments, and for most proteins these experiments have not yet been done. Computing the shape from genetic information alone is possible in principle. But despite limited success for some smaller proteins, this challenge has remained essentially unsolved. The difficulty lies in the enormous complexity of the search space, an astronomically large number of possible shapes. Without any shortcuts, it would take a supercomputer many years to explore all possible shapes of even a small protein.

"Experimental structure determination has a hard time keeping up with the explosion in genetic sequence information," said Debora Marks, a mathematical biologist in the Department of Systems Biology at HMS, who worked closely with Lucy Colwell, a mathematician, who recently moved from Harvard to Cambridge University. They collaborated with physicists Riccardo Zecchina and Andrea Pagnani in Torino in a team effort initiated by Marks and computational biologist Chris Sander of the Computational Biology Program at MSKCC, who had earlier attempted a similar solution to the problem, when substantially fewer sequences were available.

"Collaboration was key," Sander said. "As with many important discoveries in science, no one could provide the answer in isolation."

The international team tested a bold premise: That evolution can provide a roadmap to how the protein folds. Their approach combined three key elements: evolutionary information accumulated for many millions of years; data from high-throughput genetic sequencing; and a key method from statistical physics, co-developed in the Torino group with Martin Weigt, who recently moved to the University of Paris.

Using the accumulated evolutionary information in the form of the sequences of thousands of proteins, grouped in protein families that are likely to have similar shapes, the team found a way to solve the problem: an algorithm to infer which parts of a protein interact to determine its shape. They used a principle from statistical physics called "maximum entropy" in a method that extracts information about microscopic interactions from measurement of system properties.

"The protein folding problem has been a huge combinatorial challenge for decades," said Zecchina, "but our statistical methods turned out to be surprisingly effective in extracting essential information from the evolutionary record."

With these internal protein interactions in hand, widely used molecular simulation software developed by Axel Brunger at Stanford University generated the atomic details of the protein shape. The team was for the first time able to compute remarkably accurate shapes from sequence information alone for a test set of 15 diverse proteins, with no protein size limit in sight, with unprecedented accuracy.

"Alone, none of the individual pieces are completely novel, but apparently nobody had put all of them together to predict 3D protein structure," Colwell said.

To test their method, the researchers initially focused on the Ras family of signaling proteins, which has been extensively studied because of its known link to cancer. The structure of several Ras-type proteins has already been solved experimentally, but the proteins in the family are larger--with about 160 amino acid residues--than any proteins modeled computationally from sequence alone.

"When we saw the first computationally folded Ras protein, we nearly went through the roof," Marks said. To the researchers' amazement, their model folded within about 3.5 angstroms of the known structure with all the structural elements in the right place. And there is no reason, the authors say, that the method couldn't work with even larger proteins.

The researchers caution that there are other limits, however: Experimental structures, when available, generally are more accurate in atomic detail. And, the method works only when researchers have genetic data for large protein families. But advances in DNA sequencing have yielded a torrent of such data that is forecast to continue growing exponentially in the foreseeable future.

The next step, the researchers say, is to predict the structures of unsolved proteins currently being investigated by structural biologists, before exploring the large uncharted territory of currently unknown protein structures.

"Synergy between computational prediction and experimental determination of structures is likely to yield increasingly valuable insight into the large universe of protein shapes that crucially determine their function and evolutionary dynamics," Sander said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject. This research was funded by the National Cancer Institute and the Engineering and Physical Sciences Research Council of the United Kingdom.
Written by R. Alan Leo.
Citation: PLoS ONE, December 6, 2011 "Protein 3D structure computed from evolutionary sequence variation," Marks et al.
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Supercomputer Reveals New Details Behind Drug-Processing Protein Model

Main Category: Pharma Industry / Biotech Industry
Also Included In: IT / Internet / E-mail
Article Date: 08 Dec 2011 - 1:00 PST

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Supercomputer simulations at the Department of Energy's Oak Ridge National Laboratory are giving scientists unprecedented access to a key class of proteins involved in drug detoxification.

Jerome Baudry and Yinglong Miao, who are jointly affiliated with ORNL and the University of Tennessee, have performed simulations to observe the motions of water molecules in a class of enzymes called P450s. Certain types of P450 are responsible for processing a large fraction of drugs taken by humans.

The supercomputer simulations were designed to help interpret ongoing neutron experiments.

"We simulated what happens in this enzyme over a time scale of 0.3 microseconds, which sounds very fast, but from a scientific point of view, it's a relatively long time," Baudry said. "A lot of things happen at this scale that had never been seen before. It's a computational tour de force to be able to follow that many water molecules for that long."

The team's study of the water molecules' movements contributes to a broader understanding of drug processing by P450 enzymes. Because some populations have a slightly different version of the enzymes, scientists hypothesize that mutations could partially explain why people respond differently to the same drug. One possibility is that the mutations might shut down the channels that bring water molecules in and out of the enzyme's active site, where the chemical modification of drugs takes place. This could be investigated by using the computational tools developed for this research.

By simulating how water molecules move in and out of the protein's centrally located active site, the team clarified an apparent contradiction between experimental evidence and theory that had previously puzzled researchers. X-ray crystallography, which provides a static snapshot of the protein, had shown only six water molecules present in the active site, whereas experimental observations indicated a higher number of water molecules would be present in the enzyme.

"We found that even though there can be many water molecules -- up to 12 at a given time that get in and out very quickly -- if you look at the average, those water molecules prefer to be at a certain location that corresponds to what you see in the crystal structure," Miao said. "It's a very dynamic hydration process that we are exploring with a combination of neutron scattering experiments and simulation."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pharma industry / biotech industry section for the latest news on this subject. The simulation research is published in Biophysical Journal as "Active-Site Hydration and Water Diffusion in Cytochrome P450cam: A Highly Dynamic Process."
The team was supported by an Experimental Program to Stimulate Competitive Research (EPSCOR) grant from the DOE Office of Science and funding from the University of Tennessee. Computing time on the Kraken supercomputer was supported by a National Science Foundation TeraGrid award.
ORNL is managed by UT-Battelle for the Department of Energy's Office of Science.
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Evaluation Method Supports Soy Protein As A High-Quality Protein Similar To Meat, Eggs And Dairy

Main Category: Nutrition / Diet
Article Date: 08 Dec 2011 - 1:00 PST

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The importance of protein in the human body is undeniable. However, the idea of what makes a protein a "quality protein" has not been as easy to determine. A new study from the Journal of Agriculture and Food Chemistry takes a closer look at the criteria for determining the quality of a protein.

Traditional methods for determining protein quality have shown animal proteins such as milk and eggs to be high in quality. However, those who are interested in a plant-based diet, or diversifying their proteins, have a more difficult time determining which of their choices are high in quality. Testing methods have shown most plant proteins, such as pea protein, are lower in quality than animal-based proteins.

"Accurate methods for determining protein quality are key to helping people plan a healthful diet," said Glenna Hughes, MS, research scientist at Solae. "Due to the increasing interest in including plant-based proteins in the diet, accurate information on protein quality is needed in scientific literature to help educate consumers and healthcare professionals on this topic."

The Food and Agriculture Organization (FAO) and the World Health Organization (WHO) recommend using the protein digestibility-corrected amino acid score (PDCAAS) as a simple and scientific procedure for assessing protein quality. The PDCAAS methodology focuses on three different parameters: the amount of each essential amino acid the protein contains, how easily the protein can be digested, and by taking both of those parameters into account, whether the protein meets the FAO/WHO's amino acid requirements set for children aged two to five years, as they have higher needs to support growth and development than adults.

According to this study, soy protein has a PDCAAS of 1.00, meaning it is a high-quality protein that meets the needs of both children and adults. Eggs, dairy and meat proteins also have a PDCAAS score of 1.0.

However, soy protein is the only widely available high-quality plant-based protein that achieves this score.

"It's important for people to understand that a plant-based diet is healthy, but that not all proteins are created equal," said Connie Diekman, RD, LD, FADA. "If you are planning a vegetarian diet or want to incorporate plant-based proteins in your diet, understanding protein quality using the PDCAAS scale can allow you to select proteins that score higher, such as soy, to ensure that you are getting the essential amino acids you need."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our nutrition / diet section for the latest news on this subject. For more information on the study, the following is a link to the abstract: http://www.ncbi.nlm.nih.gov/pubmed/22017752.
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