Protein component apparently plays key role in muscle elasticity

November 03, 1999

CHAMPAIGN, Ill. - A pair of hydrogen bonds in the protein titin appears to be a key component allowing muscle to stretch and return to normal by regulating the ability of the protein to unfold one section at a time when stressed, researchers say.

The findings were reported in the Nov. 4 issue of the journal Nature. They are a big step forward in the basic understanding of the protein's role in controlling muscle elasticity, such as in cardiac muscular diseases, said Klaus Schulten, the director of the theoretical biophysics group at the University of Illinois Beckman Institute for Advanced Science and Technology.

Using atomic force microscopes and advanced computer-driven simulations, researchers found that the hydrogen bonds allow all folded subsections (immunoglobulin domains) of titin to stretch by about 6 angstroms and still return to a normal state. Beyond that, the bonds will rupture and domain unfolding occurs. Titin contains roughly 100 immunoglobulin domains, connected like knots on a string; when titin is stretched, the domains unfold one after another, each providing additional length.

The computer simulation allowed the researchers to observe fine mechanical details. When several connected domains are stretched with an atomic force microscope, a graph of the unfolding process displays a hump that disappears as the domains are unfolded. The hump corresponds to the transition of fully folded domains to a newly discovered intermediate state. The simulations identified which hydrogen bonds must break for the transition to occur. "Disruption of these hydrogen bonds eliminates the unfolding intermediate,"said Schulten, the Swanlund Professor of Physics at the U. of I. "The unfolding intermediate can extend the titin by 15 percent of its slack length without causing a complete unraveling of its modules, and hence is likely to be an important component of titin elasticity." At this extension, he added, "the protein will fully unfold if the forces increase, or it will return to its original state if the forces decrease."

Titin has been implicated in heart-muscle diseases such as hypertrophic cardiomyopathy, in which muscle cells break from normal alignment, possibly as a result of mutations in genes that encode proteins involved in contraction. The Hypertrophic Cardiomyopathy Association estimates that as many as 300,000 people in the United States may have the disease.

Previously, it was found that elasticity is controlled in titin's PEKV region - named for amino acids. The new work suggests that when the protein stretches within the reversible 6-angstrom-per -domain range, elasticity is controlled by the hydrogen bonds that connect two specific protein strands.

The authors of the paper were Piotr E. Marszalek, Hongbin Li, Mariano Carrion-Vazquez, Andres F. Oberhauser and Julio M. Fernandez of the Mayo Foundation in Rochester, Minn., and Hui Lu and Schulten of the U. of I. The National Institutes of Health, National Science Foundation and the Roy J. Carver Charitable Trust funded the research.
-end-


University of Illinois at Urbana-Champaign

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