Featured Research

from universities, journals, and other organizations

Unprecedented view of protein folding may help develop brain disease therapies

Date:
March 16, 2011
Source:
Stanford University
Summary:
When vital proteins in our bodies are misfolded, debilitating diseases can result. If researchers could see the folding happen, they might be able to design treatments for some of these diseases. But many of our most critical proteins are folded, hidden from sight, inside tiny molecular chambers. Now researchers have gotten the first-ever peek inside one of these protein-folding chambers as the folding happened, and the folding mechanism they saw surprised them.

Biology Professor Judith Frydman and graduate student Nicholai Douglas, who was first author on the paper published in Cell.
Credit: L.A. Cicero

When vital proteins in our bodies are misfolded, debilitating diseases can result. If researchers could see the folding happen, they might be able to design treatments for some of these diseases or even keep them from occurring. But many of our most critical proteins are folded, hidden from sight, inside tiny molecular chambers. Now researchers at Stanford have gotten the first-ever peek inside one of these protein-folding chambers as the folding happened, and the folding mechanism they saw surprised them.

Misfold an origami swan and the worst that happens is you wind up with an ugly paper duckling. Misfold one of the vital proteins in your body -- each of which must be folded in a particular way to perform its function -- and the result can be a debilitating neurodegenerative disease such as Alzheimer's or Huntington's.

There are no cures for such brain-wasting diseases, but now Stanford researchers have taken an important step that may one day aid in developing therapies for them. They have literally popped the lid off one of the microscopic chambers in which many of life's most crucial proteins are folded, witnessing a surprising mechanism as the heretofore hidden folding process happened before their eyes.

Virtually all proteins need to be folded, whether in primitive organisms such as bacteria or multicellular creatures such as humans. Many are guided through the process by molecules called chaperones, of which a specialized subset -- chaperonins -- folds many of the most complex proteins.

Folding in bacteria has been studied in detail, but Judith Frydman, a professor of biology who led the Stanford research, said this is the first time anyone has seen the folding process performed in higher organisms.

"The mechanism of folding we saw in the chaperonin is very different from what we expected and from what has been seen in bacteria," Frydman said. "It was really surprising, and we are still amazed that it worked. This chaperonin appears to provide a unique chemical environment."

Chaperonins are shaped like a barrel, with two ring-shaped chambers arranged one atop the other. At the open end of each ring is a lid that opens and closes in a spiraling fashion, like the aperture of a camera, something Frydman's team discovered in 2008 while studying the chaperonin called TRiC. Since then, they've been working to solve the puzzle of how a protein gets folded once the chaperonin has grabbed it, pulled it into the chamber and the aperture has closed. A paper describing their findings was published earlier this year in Cell.

Frydman said there were two likely ways in which a protein, initially a linear chain of molecules (amino acids), could theoretically be folded inside the chamber.

One is by mechanical means, with the chamber holding onto the protein and physically pushing it into the right shape.

"The other one is that when the lid closes, the chaperonin lets go of the protein, but some special chemical properties in this chamber somehow make it fold," she said. "Our evidence is that this mechanism is the correct one."

The only way to know which mechanism was doing the work was to see inside the chamber while the folding was happening, but simply opening up the lid wouldn't work, because the shape of the entire chamber changes in accordance with the motion of the lid. When the lid spirals open, the walls of the chamber spiral open, too, and the protein floats away.

To see what was happening, Frydman's team devised a chemical "trick" by which they could remove the lid on the chamber, but still get the walls of the chamber to close in, as if the lid were spiraling.

When they "closed" the lidless chamber, the chaperonin simply released the protein that had been destined to be folded. Like a long balloon that slipped from a child's grip before it could be folded into a giraffe, the protein simply drifted off.

The challenge then became figuring out how the protein was getting released.

"One of the reasons why the mechanical model of pushing the protein into shape without letting go had been proposed was because there was no obvious way for this chaperonin to let go of the protein," Frydman said.

When a protein gets grabbed for folding by TRiC, it is held by eight binding sites along the walls of the chamber. Between each binding site is a tiny loop. Frydman's team suspected that during the closing process, the loops might move to somehow "shave off" the protein and release it into the folding chamber. One of her students made mutations in the loop. When the researchers did experiments in which TRiC chaperonins equipped with mutated loops were closed, the protein stayed put. It also failed to fold.

"That suggests that the way this chaperonin folds its proteins is by releasing them in a closed chamber that has very special chemical properties," Frydman said.

"This mechanism of release is completely different from what has been seen in any other chaperone. That was very, very surprising."

The experimental work described in the Cell paper was done using a simpler version of TRiC, from a single-celled organism, than would be found in multi-cellular organisms, Frydman said, because the simpler version is much easier to manipulate.

"Now we are interested in going back to the eukaryotic [multi-cellular] complex, where every binding site in the folding chamber is different and every release loop is different," Frydman said. "I think this really opens up a lot of interesting avenues to explore how this works in higher organisms. Since TRiC helps fold many disease-linked proteins, and is central to protect cells from misfolding diseases such as Huntington's disease, this work could have many therapeutic applications."


Story Source:

The above story is based on materials provided by Stanford University. The original article was written by Louis Bergeron. Note: Materials may be edited for content and length.


Journal Reference:

  1. Nicholai R. Douglas, Stefanie Reissmann, Junjie Zhang, Bo Chen, Joanita Jakana, Ramya Kumar, Wah Chiu, Judith Frydman. Dual Action of ATP Hydrolysis Couples Lid Closure to Substrate Release into the Group II Chaperonin Chamber. Cell, 2011; 144 (2): 240 DOI: 10.1016/j.cell.2010.12.017

Cite This Page:

Stanford University. "Unprecedented view of protein folding may help develop brain disease therapies." ScienceDaily. ScienceDaily, 16 March 2011. <www.sciencedaily.com/releases/2011/03/110315163217.htm>.
Stanford University. (2011, March 16). Unprecedented view of protein folding may help develop brain disease therapies. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2011/03/110315163217.htm
Stanford University. "Unprecedented view of protein folding may help develop brain disease therapies." ScienceDaily. www.sciencedaily.com/releases/2011/03/110315163217.htm (accessed October 21, 2014).

Share This



More Plants & Animals News

Tuesday, October 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

'Cadaver Dog' Sniffs out Human Remains

'Cadaver Dog' Sniffs out Human Remains

AP (Oct. 21, 2014) Where's a body buried? Buster's nose can often tell you. He's a cadaver dog, specially trained to find human remains and increasingly being used by law enforcement and accepted in courts. These dogs are helping solve even decades-old mysteries. (Oct. 21) Video provided by AP
Powered by NewsLook.com
White Lion Cubs Born in Belgrade Zoo

White Lion Cubs Born in Belgrade Zoo

AFP (Oct. 20, 2014) Two white lion cubs, an extremely rare subspecies of the African lion, were recently born at Belgrade Zoo. They are being bottle fed by zoo keepers after they were rejected by their mother after birth. Duration: 00:42 Video provided by AFP
Powered by NewsLook.com
Traditional Farming Methods Gaining Ground in Mali

Traditional Farming Methods Gaining Ground in Mali

AFP (Oct. 20, 2014) He is leading a one man agricultural revolution in Mali - Oumar Diatabe uses traditional farming methods to get the most out of his land and is teaching others across the country how to do the same. Duration: 01:44 Video provided by AFP
Powered by NewsLook.com
Goliath Spider Will Give You Nightmares

Goliath Spider Will Give You Nightmares

Buzz60 (Oct. 20, 2014) An entomologist stumbled upon a South American Goliath Birdeater. With a name like that, you know it's a terrifying creepy crawler. Sean Dowling (@SeanDowlingTV) has the details. Video provided by Buzz60
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Plants & Animals

Earth & Climate

Fossils & Ruins

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins