Collin Stultz, an associate professor of electrical engineering and computer science. PHOTO: M. SCOTT BRAUER Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson's disease and Alzheimer's disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein.
MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson's, and found that it can take on either of two proposed states—floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson's, says Collin Stultz, an associate professor of electrical engineering and computer science at MIT.
"If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating," says Stultz, who is the senior author of a paper describing the findings in a recent issue of the Journal of the American Chemical Society.
For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011 Harvard University neurologist Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure.
That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Thomas Pochapsky and Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein.
Stultz and his group decided to jump into the fray, working with Pochapsky's lab, and developed a computer-modeling approach to predict what kind of structures the protein might take. Working with the structural data obtained by the Brandeis researchers, Stultz created a model that calculates the probabilities of many different possible structures, to determine what set of structures would best explain the experimental data.
The calculations suggest that the protein can rapidly switch among many different conformations. At any given time, about 70 percent of individual proteins will be in one of the many possible disordered states, which exist as single molecules of the alpha synuclein protein. When three or four of the proteins join together, they can assume a mix of possible rigid structures, including helices and beta strands (protein chains that can link together to form sheets).
"On the one hand, the people who say it's disordered are right, because a majority of the protein is disordered," Stultz says. "And the people who would say that it's ordered are not wrong; it's just a very small fraction of the protein that is ordered."
"This paper seems to bridge the gap" between the two camps, says Trevor Creamer, an associate professor of molecular and cellular biochemistry at the University of Kentucky who was not involved in this research. Also important is the model's prediction of new structures for the protein that experimental biologists can now look for, Creamer adds.
The MIT researchers also found that when alpha synuclein adopts an ordered structure, similar to that described by Selkoe and co-workers, the portions of the protein that tend to aggregate with other molecules are buried deep within the structure, explaining why those ordered forms do not clump together.
Stultz is now working to figure out what controls the protein's configuration. There is some evidence that other molecules in the cell can modify alpha synuclein, forcing it to assume one conformation or another.
"If this structure really does exist, we have a new way now of potentially designing drugs that will prevent aggregation of alpha synuclein," he says.
Explore further: Yeast protein breaks up amyloid fibrils and disease protein clumps differently
This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and teaching.
6 hours ago If we add br2 / hv to (s)-1,2-dibromobutane. Where would the radical bromine go? The book hints that the product is an optically inactive substance.... 19 hours ago Hi guys, I'm having a bit of difficulty understanding Pourboix diagrams. The biggest problem at the moment is that I don't clearly understand what... 20 hours ago Hi to all, I want to know the temperature after combustion of methane with air. How will i calculate it? Kindly inform me. Regards,... Apr 28, 2013 I am familiar with the equation ?G=?G°+RT ln(Q).But I can't derive it.We have to use the equation to derive nernst equation. So please help. Apr 28, 2013 Hi, can someone please explain to me how I can identify which is the oxidation half and which is the reduction half of a redox reaction. I have read... Apr 27, 2013 I have been urinating into a plastic bottle lately (I will not elaborate why), and have been finding the bottle to hold a vacuum the following... Jul 11, 2011 A small protein called SUMO might prevent the protein aggregations that typify Parkinson's disease (PD), according to a new study in the July 11, 2011, issue of The Journal of Cell Biology.
Oct 24, 2011 A team of researchers from the Petsko-Ringe and Pochapsky laboratories at Brandeis have produced and determined the structure of alpha-synuclein, a key protein associated with Parkinson’s disease.
Jun 17, 2011 Researchers at the Keck School of Medicine of the University of Southern California (USC) have uncovered structural clues about the protein linked to Parkinson's disease (PD), which ultimately could lead to finding a cure ...
Apr 16, 2012 Injection of a small amount of clumped protein triggers a cascade of events leading to a Parkinson's-like disease in mice, according to an article published online this week in the Journal of Experimental Medicine.
16 hours ago (Phys.org) —While the natural world is replete with compounds that form the basis of many disease-fighting pharmaceuticals, it is also the case that humans and other mammals produce their own host-defense ...
21 hours ago (Phys.org) —There's hope for patients with myotonic dystrophy. A new small molecule developed by researchers at the University of Illinois has been shown to break up the protein-RNA clusters that cause ...
Apr 29, 2013 (Phys.org) —A combined team of researchers from the U.S. and Slovenia has succeeded in creating "origami" type proteins that assemble themselves into three dimensional shapes. As a proof of concept, the ...
Apr 25, 2013 (Phys.org) —Changes in the bases that make up DNA act as markers, telling a cell which genes it should read and which it shouldn't. In the journal Angewandte Chemie, a British team has now introduced a new ...
New research at MIT could dramatically improve the efficiency of fuel cells, which are considered a promising alternative to batteries for powering everything from electronic devices to cars and homes.
(Phys.org) —While the natural world is replete with compounds that form the basis of many disease-fighting pharmaceuticals, it is also the case that humans and other mammals produce their own host-defense ...
(Phys.org) —In 2012, more than 3 million people had stents inserted in their coronary arteries. These tiny mesh tubes prop open blood vessels healing from procedures like a balloon angioplasty, which widens ...
(Phys.org) —There's hope for patients with myotonic dystrophy. A new small molecule developed by researchers at the University of Illinois has been shown to break up the protein-RNA clusters that cause ...
From methanol to formaldehyde - this reaction is the starting point for the synthesis of many everyday plastics. Using catalysts made of gold particles, formaldehyde could be produced without the environmentally ...
Just as people have embraced computers and smart phones, they may also give their blessing to talking tissue boxes and other smart objects, according to Penn State researchers.
Although eleventh-century Vikings did not have magnetic compasses at their disposal, it is thought that they could determine their orientation at sea using sun-compasses. Sun-compasses use the position of ...
A tiny bird fossil discovered in Wyoming offers clues to the precursors of swift and hummingbird wings. The fossil is unusual in having exceptionally well-preserved feathers, which allowed the researchers ...
A new study by researchers in the Center for Injury Research and Policy of The Research Institute at Nationwide Children's Hospital examined injuries to children related to amusement rides, which included ...
Elderly patients who receive anesthesia are no more likely to develop long-term dementia or Alzheimer's disease than other seniors, according to new Mayo Clinic research. The study analyzed thousands of patients using the ...
© Phys.org™ 2003-2013var _comscore = _comscore || [];var csDocDomain = document.location.href; _comscore.push({ c1: "2", c2: "6035753", c3: "6035753", c4: csDocDomain }); (function() { var s = document.createElement("script"), el = document.getElementsByTagName("script")[0]; s.async = true; s.src = (document.location.protocol == "https:" ? "https://sb" : "http://b") + ".scorecardresearch.com/beacon.js"; el.parentNode.insertBefore(s, el);})();
No comments:
Post a Comment