Featured Research

from universities, journals, and other organizations

Engineers probe mechanics behind rapid-aging disease

Date:
September 14, 2011
Source:
Massachusetts Institute of Technology
Summary:
Researchers are using both civil engineering and bioengineering approaches to study the behavior of a protein associated with progeria, a rare disorder in children that causes extremely rapid aging and usually ends in death from cardiovascular disease before age 16. The disease is marked by the deletion of 50 amino acids near the end of the lamin A protein, which helps support a cell's nuclear membrane. Pulling the tail of mutated protein could help illuminate problems with misfolding.

Researchers at MIT and Carnegie Mellon University are using both civil engineering and bioengineering approaches to study the behavior of a protein associated with progeria, a rare disorder in children that causes extremely rapid aging and usually ends in death from cardiovascular disease before age 16. The disease is marked by the deletion of 50 amino acids near the end of the lamin A protein, which helps support a cell's nuclear membrane.

At MIT, the researchers used molecular modeling -- which obeys the laws of physics at the molecular scale -- to simulate the behavior of the protein's tail under stress in much the same way a traditional civil engineer might test the strength of a beam: by applying pressure. In this instance, they created exact replicas of healthy and mutated lamin A protein tails, pulling on them to see how they unraveled.

"The application of engineering mechanics to understand the process of rapid aging disease may seem odd, but it actually makes a lot of sense," says Markus Buehler, a professor in MIT's Department of Civil and Environmental Engineering who also studies structural proteins found in bone and collagen. In this new research, he worked with Kris Dahl, professor of biomedical engineering and chemical engineering at Carnegie Mellon, and graduate students Zhao Qin of MIT and Agnieszka Kalinowski of Carnegie Mellon. They published their findings in the September issue of the Journal of Structural Biology.

In its natural state, a protein -- and its tail -- exist in complex folded configurations that differ for each protein type. Many misfolded proteins are associated with diseases. In molecular simulations, Qin and Buehler found that the healthy lamin A protein tail unravels sequentially along its backbone strand, one amino acid at a time.

"It behaved much as if I pulled on a loose thread on my shirt cuff and watched it pull out stitch by stitch," said Qin.

By contrast, the mutant protein tail, when pulled, first breaks nearly in half, forming a large gap near the middle of its folded structure, then begins unfolding sequentially. The MIT scientists deduced that it takes an additional 70 kilocalories per mole (a unit of energy) to straighten the mutant tails, meaning the mutant protein is actually more stable than its healthy counterpart.

At Carnegie Mellon, Dahl and Kalinowski studied the same topic by subjecting lamin A protein tails to heat, which causes proteins to denature or unfold. In their lab, they observed the same pattern of unraveling in healthy and mutated proteins as the MIT engineers did in their atomistic simulation.

Qin then wrote a mathematical equation to convert the temperature differential seen in denaturing the mutant and healthy proteins (4.7 degrees Fahrenheit) to the unit of energy found in the atomistic simulations, finding that the increase in temperature very nearly matched the increase in energy. This agreement, the researchers say, validates the application of the civil engineering methodology to the study of the mutated protein in diseased cells.

The results, however, were counterintuitive to the civil engineers, who are accustomed to flawed materials being weaker -- not stronger -- than their unimpaired counterparts.

As a component of the cell's nucleoskeleton, lamin A plays an important role in defining the mechanical properties of a cell's nuclear membrane, which must remain flexible enough to easily withstand deformation. In previous work, Dahl had observed that nuclear membranes built from the mutated proteins become very stiff and brittle, which could explain the altered protein-DNA and protein-protein interactions observed in diseased cells.

"Our surprising finding is that the defective mutant structure is actually more stable and more densely packed than the healthy protein," said Buehler. "This is contrary to our intuition that a 'defective' structure is less stable and breaks more easily, which is what engineers would expect in building materials. However, the mechanics of proteins is governed by the principles of nanomechanics, which can be distinct from our conventional understanding of materials at the macro scale."


Story Source:

The above story is based on materials provided by Massachusetts Institute of Technology. Note: Materials may be edited for content and length.


Journal Reference:

  1. Zhao Qin, Agnieszka Kalinowski, Kris Noel Dahl, Markus J. Buehler. Structure and stability of the lamin A tail domain and HGPS mutant. Journal of Structural Biology, 2011; 175 (3): 425 DOI: 10.1016/j.jsb.2011.05.015

Cite This Page:

Massachusetts Institute of Technology. "Engineers probe mechanics behind rapid-aging disease." ScienceDaily. ScienceDaily, 14 September 2011. <www.sciencedaily.com/releases/2011/09/110914131359.htm>.
Massachusetts Institute of Technology. (2011, September 14). Engineers probe mechanics behind rapid-aging disease. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2011/09/110914131359.htm
Massachusetts Institute of Technology. "Engineers probe mechanics behind rapid-aging disease." ScienceDaily. www.sciencedaily.com/releases/2011/09/110914131359.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Nigeria Ups Ebola Stakes on 1st Death

Nigeria Ups Ebola Stakes on 1st Death

Reuters - Business Video Online (July 29, 2014) Nigerian authorities have shut and quarantined a Lagos hospital where a Liberian man died of the Ebola virus, the first recorded case of the highly-infectious disease in Africa's most populous economy. David Pollard reports Video provided by Reuters
Powered by NewsLook.com
Running 5 Minutes A Day Might Add Years To Your Life

Running 5 Minutes A Day Might Add Years To Your Life

Newsy (July 29, 2014) According to a new study, just five minutes of running or jogging a day could add years to your life. Video provided by Newsy
Powered by NewsLook.com
Ebola Outbreak Poses Little Threat To U.S.: CDC

Ebola Outbreak Poses Little Threat To U.S.: CDC

Newsy (July 29, 2014) The Ebola outbreak in West Africa poses little threat to Americans, according to officials with the Centers for Disease Control and Prevention. Video provided by Newsy
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:
from the past week

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