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MIT, Carnegie Mellon researchers link protein behavior to rapid-aging disease
by Amy Swinderman  |  Email the author


CAMBRIDGE, Mass.—Using civil and bioengineering approaches to study protein behavior, researchers at the Massachusetts Institute of Technology (MIT) and Carnegie Mellon University are gaining important clues about the genetic mutation that causes progeria, a rare disorder in children that causes extremely rapid aging.
Also known as Hutchinson-Gilford Progeria Syndrome, progeria is an extremely rare genetic condition caused by a de-novo mutation in which aspects of aging are manifested at an early age. 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.  
The condition is usually diagnosed when a young person experiences signs and symptoms such as skin changes, abnormal growth and loss of hair. Progeria reportedly occurs in 1 out of every 8 million live births. There is no known cure. Nearly 90 percent of progeria patients die from complication of atherosclerosis, such as heart attack or stroke. Most treatment focuses on reducing cardiovascular complications, such as heart bypass surgery or low- dose aspirin. Children may also benefit from a high-calorie diet. Growth hormone treatment has been attempted.
Scientists are also interested in progeria because it might reveal clues about the normal process of aging.  
Publishing their findings in the September issue of the Journal of Structural Biology, the MIT/Carnegie Mellon team describe how they applied engineering mechanics to understand the process of rapid aging disease—which may seem odd, says Markus Buehler, a professor in MIT's Department of Civil and Environmental Engineering, "but it actually makes a lot of sense," he adds.  
Buehler's lab studies the structural proteins found in bone and collagen, and how protein materials define our bodies and how they fail catastrophically.  
At MIT, the researchers used molecular modeling to simulate the behavior of the lamin A protein's tail under stress and applied pressure—much like how a traditional civil engineer might test the strength of a beam. They created exact replicas of healthy and mutated lamin A protein tails and pulled on them to see how they unraveled.  
In molecular simulations, the healthy lamin A protein tail unraveled sequentially along its backbone strand, one amino acid at a time—behaving "much as if I pulled on a loose thread on my shirt cuff and watched it pull out stitch by stitch," said MIT graduate student Zhao Qin.  
In contrast, the mutant protein tail, when pulled, first broke nearly in half, forming a large gap near the middle of its folded structure, then began unfolding sequentially. The MIT lab observed that it takes an additional 70 kilocalories per mole to straighten the mutant tails. Thus, the mutant protein is actually more stable than its healthy counterpart.  
From there, MIT's colleagues at Carnegie Mellon—Kris Dahl, professor of biomedical engineering and chemical engineering, and graduate student Agnieszka Kalinowski—subjected lamin A protein tails to heat, causing the proteins to denature or unfold. They observed the same pattern of unraveling in healthy and mutated proteins. 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.  
The Carnegie Mellon researchers observed 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.  
However, these results were actually counterintuitive to the civil engineers, who are accustomed to flawed materials being weaker than their healthy counterparts.  
"Our surprising finding is that the defective mutant structure is actually more stable and more densely packed than the healthy protein," Buehler told MIT's media department. "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."      

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