Featured Research

from universities, journals, and other organizations

Physicists manipulate single molecules to unravel secrets of protein folding

Date:
December 8, 2011
Source:
Technische Universitaet Muenchen
Summary:
Physicists are opening a new window on protein folding, using a technique that lets them grab the ends of a single protein molecule and pull, making continuous, direct measurements as it unfolds and refolds. The latest study of the protein calmodulin reveals a complex network of intermediate states along the way to functionally correct folded forms. Better understanding of protein folding is essential because incorrectly folded proteins cause diseases such as Alzheimer's and Parkinson's.

Grabbing a single molecule.
Credit: Johannes Stigler / TUM

Physicists at the Technische Universitaet Muenchen (TUM) are opening a new window into the life of biological cells, using a technique that lets them grab the ends of a single protein molecule and pull, making continuous, direct measurements as it unfolds and refolds. Their latest results, reported in the journal Science, reveal a complex network of intermediate structural and kinetic states along the way to functionally correct folded forms, including both express routes and dead ends. Better understanding of protein folding is essential because incorrectly folded proteins cause diseases such as Alzheimer's and Parkinson's.

Related Articles


The experiments focused on the protein calmodulin, which is not implicated in these diseases but plays a role in many processes vital to cellular functions, and thus to human health.

The functions (and malfunctions) of proteins are largely determined by their structures, so researchers are exploring many avenues toward understanding precisely how they fold (or misfold). Where X-ray structural analyses offer "snapshots" of protein folding, single-molecule force spectroscopy -- the approach pioneered by Prof. Matthias Rief and colleagues in the TUM Department of Physics -- produces views that are, by comparison, more like movies. Even though these movies are very "blurred," since they only capture the length of the molecule, they allow the researchers to study the dynamics of the folding process.

In the study reported in Science, Rief's co-authors were TUM doctoral candidates Johannes Stigler, Fabian Ziegler, Anja Gieseke, and Christof Gebhardt (now a postdoc at Harvard University). A grant from the TUM Institute for Advanced Study helped the laboratory acquire the instrumentation that made these single-molecule experiments possible -- ultra-stable, high-resolution "optical tweezers," a tool that traps miniscule objects between opposing laser beams as surely as if they were being held between thumb and forefinger.

To get a grip on a calmodulin molecule, the researchers first would insert it between two molecules of a mechanically tougher protein called ubiquitin. Residues of the amino acid cysteine at the outer ends of this assembly allowed "handles" made of DNA to be attached, and these were fixed to glass beads one micrometer in diameter. The beads, and thus the calmodulin molecule between them, could then be manipulated with the optical tweezers. The essence of the experiments, repeated many times over in a variety of ways, was to pull the ends of a single, folded calmodulin molecule until it straightened out and then to reduce the tension so it could fold again, constantly measuring protein length, mechanical forces and time with extreme precision. Throughout, the calmodulin molecule was kept in conditions not too different from its working environment inside a cell, an aqueous solution with a concentration of calcium ions known to favor stable folding. Statistical analysis helped to reveal what the measurements recorded.

The results indicate that distinct subdomains of the calmodulin molecule fold independently yet interact with others, sometimes cooperating and sometimes interfering. "Far from being a simple two-state process," Rief explains, "the folding of a calmodulin molecule takes place via a complex network of pathways in what we call its 'energy landscape.' We found that this map of kinetic states and paths between different folded forms includes dead ends -- intermediate structures that need to be undone, like unwanted knots in a rope, before the protein can assume a shape that enables it to function properly." The researchers also discovered express routes, pathways that let some domains reach their final state much more rapidly than the molecule as a whole.

"The calmodulin molecule," Rief says, "even though considered small compared to most proteins in our body, already exhibits unexpected complexity in its folding. Nature manages to fold much more complex proteins without major misfoldings. Understanding this still remains a challenge for the future, and single-molecule experiments will help to resolve it."

This research was supported by the Deutsche Forschungsgemeinschaft (SFB 863 A2), the TUM Institute for Advanced Study (Excellence Initiative), and the Elite Network of Bavaria.


Story Source:

The above story is based on materials provided by Technische Universitaet Muenchen. Note: Materials may be edited for content and length.


Journal Reference:

  1. J. Stigler, F. Ziegler, A. Gieseke, J. C. M. Gebhardt, M. Rief. The Complex Folding Network of Single Calmodulin Molecules. Science, 2011; 334 (6055): 512 DOI: 10.1126/science.1207598

Cite This Page:

Technische Universitaet Muenchen. "Physicists manipulate single molecules to unravel secrets of protein folding." ScienceDaily. ScienceDaily, 8 December 2011. <www.sciencedaily.com/releases/2011/10/111027145844.htm>.
Technische Universitaet Muenchen. (2011, December 8). Physicists manipulate single molecules to unravel secrets of protein folding. ScienceDaily. Retrieved March 5, 2015 from www.sciencedaily.com/releases/2011/10/111027145844.htm
Technische Universitaet Muenchen. "Physicists manipulate single molecules to unravel secrets of protein folding." ScienceDaily. www.sciencedaily.com/releases/2011/10/111027145844.htm (accessed March 5, 2015).

Share This


More From ScienceDaily



More Matter & Energy News

Thursday, March 5, 2015

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gas Production Cut on Earthquake Fears

Gas Production Cut on Earthquake Fears

Reuters - Business Video Online (Mar. 5, 2015) The Dutch government has cut production at Europe&apos;s largest gas field in Groningen amid concerns over earthquakes which are damaging local churches. As Amy Pollock reports the decision - largely politically-motivated - could have big economic conseqeunces. Video provided by Reuters
Powered by NewsLook.com
Star Wars-Inspired Prototype Creates Holographic Display

Star Wars-Inspired Prototype Creates Holographic Display

Reuters - Innovations Video Online (Mar. 5, 2015) A prototype holographic display named Leia - after the Star Wars princess who appeared in holographic form asking Obi-Wan Kenobu for help - is demonstrated at the Mobile World Congress in Barcelona. Matthew Stock reports. Video provided by Reuters
Powered by NewsLook.com
IKEA and Samsung Launch Embedded Wireless Charging Range

IKEA and Samsung Launch Embedded Wireless Charging Range

Reuters - Innovations Video Online (Mar. 5, 2015) Samsung and IKEA hope their new embedded wireless charging products, launched at Barcelona&apos;s Mobile World Congress, will tempt consumers eager for plugless power. Jim Drury reports. Video provided by Reuters
Powered by NewsLook.com
Samsung Unveils $30,000 'Dream Doghouse'

Samsung Unveils $30,000 'Dream Doghouse'

Buzz60 (Mar. 5, 2015) On display at the Crufts dog show in England, the &apos;dog kennel of the future&apos; comes with features like a doggie treadmill and Samsung tablet. Mike Janela (@mikejanela) has more. 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


Space & Time

Matter & Energy

Computers & Math

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