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Engineers probe mechanics behind rapid-aging disease
Date:9/14/2011

ein 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 stabl
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Contact: Marta Buczek
mbuczek@mit.edu
617-721-5749
Massachusetts Institute of Technology
Source:Eurekalert

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