all proteins stories

Comprehensive model first to map protein folding at atomic level

Thu, 12 Jul 2007 09:53:08 -0400

Scientists at Harvard University have developed a computer model that, for the first time, can fully map and predict how small proteins fold into three-dimensional, biologically active shapes. The work could help researchers better understand the abnormal protein aggregation underlying some devastating diseases, as well as how natural proteins evolved and how proteins recognize correct biochemical partners within living cells.

The technique, which can track protein folding for some 10 microseconds - about as long as some proteins take to assume their biologically stable configuration, and at least a thousand times longer than previous methods - is described this week in the Proceedings of the National Academy of Sciences (PNAS).

Researchers discover mechanism that regulates bone growth

Fri, 13 Jul 2007 09:35:58 -0400

Harvard researchers have identified a protein that helps regulate bone growth and may lead to new drug targets to fight osteoporosis, the bone loss condition that the National Institutes of Health terms "a major public health threat" to more than half of people age 50 or older.

The research, conducted by scientists at the Harvard School of Public Health and Harvard Medical School, identified a protein in mice called Schnurri-3 that when absent results in dramatic increases in bone mass.

Discovery of calcium channel protein illuminates T cell signaling

70652986 — Mon, 26 Mar 2007 06:26:42 -0400

A rare genetic defect in a family has helped researchers identify a key signaling component in T cells.

The newly identified protein, Orai1, may be a piece of a long- sought calcium channel in T cells that is critical for lymphocyte function. When two siblings inherited two copies of a mutant form of Orai1, it caused a severe impairment of their immune systems.

Now, more than a decade after their case was reported, Yousang Gwack and Stefan Feske in Anjana Rao's lab have found the protein responsible for the disease. Their findings appear in the April 2, 2006 Nature.

Evolution follows few possible paths to antibiotic resistance

50443248 — Wed, 18 Jul 2007 12:33:28 -0400

Darwinian evolution follows very few of the available mutational pathways to attain fitter proteins, researchers at Harvard University have found in a study of a gene whose mutant form increases bacterial resistance to a widely prescribed antibiotic by a factor of roughly 100,000. Their work indicates that of 120 harrowing, five-step mutational paths that theoretically could grant antibiotic resistance, only about 10 actually endow bacteria with a meaningful evolutionary advantage.

The research is described this week in the journal Science.

Enzyme key in preventing Alzheimer's onset

70652986 — Mon, 26 Mar 2007 07:10:50 -0400

A new discovery has found that Pin1, an enzyme previously shown to prevent the formation of the tangle-like lesions found in the brains of Alzheimer's disease patients, also plays a pivotal role in guarding against the development of amyloid peptide plaques, the second brain lesion that characterizes Alzheimer's.

These new findings, shown in an animal study, provide further evidence that Pin1 (prolyl isomerase) is essential to protect individuals from age-related neurodegeneration and for the first time establish a direct link between amyloid plaques and tau tangles, the two abnormal structures that are considered the pathological hallmarks of this devastating disease. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, the study appears in the March 23, 2006 issue of the journal Nature.

"A century ago, in 1906, the German doctor Alois Alzheimer first observed an abundance of these plaques and tangles in the brains of Alzheimer's patients," explains the study's senior author, Kun Ping Lu, MD, PhD, an investigator in the Division of Cancer Cell Biology at BIDMC and associate professor of medicine at Harvard Medical School.

"Throughout the years, intensive studies have been done to find out the causes of these two major lesions, but the exact relationship between the two has remained controversial and elusive," he adds. "Coupled with recent independent studies showing that genetic changes in the human Pin1 gene are associated with reduced Pin1 protein levels as well as an increased risk of Alzheimer's disease, these new results suggest that lack of sufficient Pin1 enzyme may be a key culprit in the onset of Alzheimer's disease."

Lu, together with Tony Hunter from the Salk Institute, first identified the Pin1 enzyme in 1995. Eight years later, in 2003, Lu and his colleagues demonstrated that Pin1 promoted dephosphorylation of tau, thereby 'detangling' the protein which had become knotted and overburdened with excess phosphate molecules. They also confirmed that when Pin1 was missing, neurons in the regions of the brain responsible for memory would collapse under the weight of the tau protein tangles, ultimately leading to age-dependent neurodegeneration.

In this new study, Lu and his coauthors hypothesized that Pin1 might be acting in a similar fashion to regulate APP (amyloid precursor protein) cleavage and amyloid beta production, thereby preventing the formation of plaques.

This study was funded in part by grants from the National Institutes of Health, the National Science Foundation and the Taiwan National Science Council.

Protein underlies brain's response to activity

70652986 — Mon, 26 Mar 2007 06:25:00 -0400

Experience helps shape the brain, but how that happens - how synapses are remodeled in response to activity - is one of neurobiology's biggest mysteries. Though axons and dendrites can be easily spotted waxing and waning under the microscope, the molecular middlemen working inside the cell to shape the neuron's sinewy processes have been much more elusive.

Two independent teams of Harvard Medical School (HMS) researchers report that they have found a protein that either pares down or promotes a neuron's synapses, depending on whether or not the neuron is being activated. Rather than work at the far reaches of the cell, in the axon or dendrite, the protein myocyte enhancer factor 2 (MEF2) resides in the nucleus, where it turns on and off genes that control dendritic remodeling. In fact, the researchers have identified some of MEF2's targets. In addition, one of the teams has identified how MEF2 switches from one program to the other, that is, from dendrite- promoting to dendrite-pruning. The discoveries are reported in back-to-back papers in the Feb. 17, 2006 Science.

The uncovering of the MEF2 pathway and its genetic switch helps fill in a theoretical blank in neurobiology, but what excites the researchers are the potential implications for the clinic. "Changes in the morphology of synapses could turn out to be very important in a whole host of diseases including neurodegenerative as well as psychiatric disorders," said Azad Bonni, HMS associate professor of pathology, who, with research fellow Aryaman Shalizi, HST medical student Brice Gaudilliére, and colleagues, authored one of the papers. Graduate student Steven Flavell and Michael Greenberg, HMS professor of neurology at Children's Hospital Boston, who led the other team, believe that the MEF2 pathway could play a role in autism and other neurodevelopmental diseases.

Early steps discovered in protein-making process

70652986 — Mon, 26 Mar 2007 06:23:28 -0400

Translation, the synthesis of protein from an mRNA template, has long been considered a benign sequela to transcription. After all, dysregulation of transcription causes a multitude of human disorders, including cancer and metabolic diseases. But it turns out that translation is not so innocuous. Recent evidence has shown that dysregulation of two proteins involved in translation, eukaryotic initiation factor 4E (eIF4E) and the S6 kinases, contributes to carcinogenesis, for example. For this reason alone, translational regulation may be getting less attention than it should.

John Blenis, Harvard Medical School professor of cell biology, and colleagues helped rectify that. In the Nov. 18, 2005 Cell, they revealed just how S6 kinase 1 (S6K1) helps to regulate the initiation of protein synthesis. The findings not only fill a huge gap in the understanding of translation, but they may also lead to new insights into the development and treatment of cancer. "We are really excited about defining the molecular basis of translation initiation, but more importantly, the findings provide the real potential for developing biomarkers that can measure inappropriate activation of this signaling pathway in cancer and other diseases," said Blenis.

Brain protein may play role in innate and learned fear

70652986 — Mon, 26 Mar 2007 05:42:30 -0400

In a paper published in the November 2005 issue of Cell, researchers reported that the protein stathmin is essential for the fear response - both the expression of innate fear and the formation of memory for learned fear.

Previous studies had shown that the amygdala, a brain structure important for emotional responses, is the place where fear memory is formed.

"This is the first time it has been shown that the protein called stathmin - the product of the stathmin gene - is linked to fear conditioning pathways," said Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean Hospital. The study is the collaborative effort of Bolshakov's lab at McLean and those of Eric Kandel at Columbia University and Gleb Shumyatsky of Rutgers. Kandel is the winner of the 2000 Nobel Prize in physiology or medicine.

The researchers for some time have been studying how changes in the brain may affect learning and memory. In earlier animal studies, Bolshakov and Kandel were able to measure changes in the brain and correlate them with changes in behavior associated with learning.

This study, using mice, demonstrated that those that were genetically modified so they would not produce stathmin showed deficits in neural transmission and exhibited decreased memory in fear conditioning and the failure to recognize danger in innately aversive environments. Learned fear develops after conditioning and lasts for life.

"The evidence that stathmin is important in the regulation of fear suggests that stathmin knockout mice can be used as a model of anxiety states or mental disorders with innate and learned fear components," the paper said.

In the future, these animal models may be used to develop new anti-anxiety drugs, Bolshakov added.

Bulyk searches for DNA on-off switches

70652986 — Mon, 26 Mar 2007 06:22:53 -0400

Martha Bulyk held what looked like an ordinary glass slide up to the large window that is much of one wall of her Harvard Medical School office. The slide seemed to be blank, but a puff of breath exposed row after row of tiny dots, appearing like the hidden writing of a secret message.

But the dots are more decoder ring than secret code, an array made up of bits of DNA that Bulyk is using to understand mysterious proteins called transcription factors that are critical in understanding DNA because they turn individual genes on and off.

"I'm interested in understanding how it is that the genome is organized," Bulyk said. "We get such complex life forms and processes and all the instructions are included in the genome somehow."

Bulyk, assistant professor of medicine, of pathology, and of health sciences and technology at Harvard Medical School, has pioneered the use of microarray technology in the analysis of transcription factors. Her advance promises to dramatically cut the time needed to characterize transcription factors and their associated genes from weeks and months to just a day.

Her work, published in December 2004 in the journal Nature Genetics, won her recognition from the Massachusetts Institute of Technology's Technology Review Magazine, which listed her among the top 35 technology innovators under age 35.

"Martha has been a pioneer in assays for DNA-protein interactions and the computational analysis of the resulting large data sets," said Harvard Medical School Genetics Professor George Church.

Scientists have long known that the blueprint of life is contained in DNA - long, double-stranded helical molecules in the nucleus of every cell in our bodies. DNA itself is made up of a series of base pairs, whose order determines everything from eye color and hair color to number of legs and body shape.

The encoded genes are put into action through a process called transcription, where a special enzyme breaks the DNA strands apart, reads the code, and creates an RNA molecule that carries that code elsewhere in the cell to be translated into action. The transcription process itself is regulated by proteins that bind to specific DNA regulatory elements on either side of the gene. It is these proteins, called transcription factors, and their DNA binding sites that have caught Bulyk's eye.

In her work with the microarrays, Bulyk and her lab team first created microarrays by dotting bits of DNA onto glass slides and then exposed the arrays to a possible transcription factor. They knew that a transcription factor would bind to the DNA at specific sites, and so they gently washed the chip to remove protein that wasn't bound. The remaining proteins, which had been tagged with a fluorescent molecule, glowed. To find what they were looking for, all the researchers had to do was look for the glowing dots.

Preparing the first 'Who's Who in Proteins'

50443248 — Fri, 20 Jul 2007 11:51:25 -0400

Proteins gone wrong cause most human diseases. Find these mutated proteins, scientists reason, and they are on the way to predicting who will get what disease. They would also learn scads of new biology to help doctors decide when to start available treatments, and to help in the search for additional treatments.
Of course, there's a big problem to address first, or someone would have done this already. Experts estimate that humans have about 100,000 proteins in each of their cells. In the daily course of living, many of those proteins interact with each other. So researchers faced the gargantuan task of cataloging an incredible number of interactions - millions, if not billions.

Learning how the SARS virus spikes its quarry

70652986 — Mon, 26 Mar 2007 06:21:52 -0400

Structural images that show how the SARS virus's spike protein grasps its receptor may help scientists learn new details about how the virus infects cells and could also help in identifying potential weak points that novel drugs or vaccines could exploit.

A worldwide SARS (severe acute respiratory syndrome) outbreak in 2002-2003 affected more than 8,000 people and killed 774 before being brought under control. Public health experts worry about another outbreak of the virus, which originates in animals such as civet cats.

The research team, led by Howard Hughes Medical Institute investigator Stephen C. Harrison at Children's Hospital and Harvard Medical School, and colleague Michael Farzan, also at Harvard Medical School, reported its findings in the September 16, 2005 issue of the journal Science.

Critical step traced in anthrax infection

70652986 — Mon, 26 Mar 2007 06:21:48 -0400

An anthrax bacterium secretes three nontoxic proteins that assemble into a toxic complex on the surface of the host cell to set off a chain of events leading to cell toxicity and death. Protective antigen (PA) is one of these proteins, and after binding to the cell, seven copies of it assemble into a specific complex that is capable of forming a pore in a cellular membrane. The pore permits the other two proteins to enter the cell interior, where the factors interfere with metabolic processes and can kill the infected individual.

The scientists demonstrated this role by investigating the channel's chemical make-up. Using cysteine-scanning mutagenesis, they identified the hydrophobic ("greasy") amino acid phenylalanine in protective antigen's pore-forming domain. Seven of these amino acids project into the lumen of the pore and form a collection of greasy residues, nicknamed "the phi- clamp" by the scientists. Because the water-filled lumen of the membrane pore is smaller than the folded lethal factor and edema factor, these proteins must first unfold before being actively translocated through the heptameric channel. The researchers demonstrated that the phi-clamp was critical to infection by mutating the region and blocking translocation of the toxin proteins.

R. John Collier, professor of microbiology and molecular genetics at HMS, and his colleagues found that the phi-clamp composes the main conductance-blocking site for hydrophobic drugs.

Researchers ID antigen for type 1 diabetes

50443248 — Tue, 24 Jul 2007 13:18:00 -0400

Type 1 diabetes, diagnosed in children and adults, is an autoimmune disease that occurs when the pancreas no longer produces insulin. Diabetes, which ranks as the fifth-deadliest disease in the United States, has reached critical proportions, affecting 18.2 million people, or 6.3 percent of the population. To address what many consider a growing epidemic, scientists at Brigham and Women's Hospital (BWH) and the Harvard Medical School (HMS) have focused their research on better understanding the mechanisms of the disease.

Repairing DNA damage

50443248 — Tue, 24 Jul 2007 16:36:05 -0400

Scientists have discovered some fascinating details about a handy repair service in your genes that that not much is known about. It searches through the huge amounts of DNA in the core of every human cell and recognizes parts that have become damaged due to the wear and tear of life. Then it removes and helps replace the faulty part without you being aware of it.
For the first time, researchers at Harvard University have taken snapshots of one of these protective "mechanics" at work. It's a protein that checks out parts known as "bases," the building blocks of DNA, which makes up our genes and carries the blueprints for our biology and behavior.

Protein packages activate genes

70652986 — Mon, 26 Mar 2007 06:17:33 -0400

It's all in the packaging. How nature wraps and tags genes determines if and when they become active, according to researchers from Harvard and M.I.T. They did the largest, most detailed study to date of the protein structure that surrounds the human genome. Their findings reveal surprising and previously unknown specifics of how genes get switched on during development of the human body and in diseases such as cancer. "Each type of cell in our bodies contains the same genes. What makes them do different things involves which genes are turned on," notes Bradley Bernstein, a pathologist at Harvard Medical School. The analysis shows a striking and surprising exception in the way some critical genes are activated by the protein packaging. The big surprise involves clusters of so-called "HOX" genes, which apparently work in concert to control how we develop in the womb. Instead of being activated individually like most genes, the HOX genes appear to be turned on in groups by massive numbers of tags. HOX genes also are deeply involved in cancer, making the findings particularly important. Some of the proteins that regulate HOX genes are capable of causing or suppressing tumors. "Many of the proteins that regulate these genes can suppress or enhance tumor growth," Bernstein notes. "Some of the genes can cause cancer directly when altered by mutations." "The work we're doing now is very fundamental," he says. "But what we learn about the interactions between chromatin, its tags, and various proteins that interact with them may one day be useful for understanding, diagnosing, and even developing new treatments for some cancers."