MIT, Carnegie Mellon researchers link protein behavior to rapid-aging disease
Also known as Hutchinson-Gilford Progeria Syndrome, progeriais an extremely rare genetic condition caused by a de-novo mutation in which aspects of aging are manifested at anearly age. The disease is marked by the deletion of 50 amino acids near the endof the lamin A protein, which helps support a cell's nuclear membrane.
The condition is usually diagnosed when a young personexperiences signs and symptoms such as skin changes, abnormal growth and lossof 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 fromcomplication of atherosclerosis, such as heart attack or stroke. Most treatmentfocuses on reducing cardiovascular complications, such as heart bypass surgeryor low-dose aspirin. Children may also benefit from a high-calorie diet. Growthhormone treatment has been attempted.
Scientists are also interested in progeria because it mightreveal clues about the normal process of aging.
Publishing their findings in the September issue of the Journal of Structural Biology, theMIT/Carnegie Mellon team describe how they applied engineering mechanics tounderstand the process of rapid aging disease—which may seem odd, says MarkusBuehler, a professor in MIT's Department of Civil and EnvironmentalEngineering, "but it actually makes a lot of sense," he adds.
Buehler's lab studies the structural proteins found in boneand collagen, and how protein materials define our bodies and how they failcatastrophically.
At MIT, the researchers used molecular modeling to simulatethe behavior of the lamin A protein's tail under stress and appliedpressure—much like how a traditional civil engineer might test the strength ofa beam. They created exact replicas of healthy and mutated lamin A proteintails and pulled on them to see how they unraveled.
In molecular simulations, the healthy lamin A protein tailunraveled sequentially along its backbone strand, one amino acid at atime—behaving "much as if I pulled on a loose thread on my shirt cuff andwatched it pull out stitch by stitch," said MIT graduate student Zhao Qin.
In contrast, the mutant protein tail, when pulled, firstbroke nearly in half, forming a large gap near the middle of its foldedstructure, then began unfolding sequentially. The MIT lab observed that ittakes 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 graduatestudent Agnieszka Kalinowski—subjected lamin A protein tails to heat, causingthe proteins to denature or unfold. They observed the same pattern ofunraveling in healthy and mutated proteins. Qin then wrote a mathematicalequation to convert the temperature differential seen in denaturing the mutantand healthy proteins (4.7 degrees Fahrenheit) to the unit of energy found inthe atomistic simulations.
The Carnegie Mellon researchers observed that the increasein temperature very nearly matched the increase in energy. This agreement, theresearchers say, validates the application of the civil engineering methodologyto the study of the mutated protein in diseased cells.
However, these results were actually counterintuitive to thecivil engineers, who are accustomed to flawed materials being weaker than theirhealthy counterparts.
"Our surprising finding is that the defective mutantstructure is actually more stable and more densely packed than the healthyprotein," Buehler told MIT's media department. "This is contrary to ourintuition that a 'defective' structure is less stable and breaks more easily,which is what engineers would expect in building materials. However, themechanics of proteins is governed by the principles of nanomechanics, which canbe distinct from our conventional understanding of materials at the macroscale."