When the walls of the heart muscles either grow thin or become too thick, it is usually the result of changes in the way proteins in the muscle fibre interact with each other. But how do these changes, or mutations, actually work and how significant are they, especially with regard to heart disease? New research from the Bangalore-based National Centre for Biological Sciences (NCBS) has demonstrated for the first time the structural changes that accompany protein interactions in their open state, which may offer a potential dimension to explain why certain mutations can lead to the health problem.
Understanding these structural changes will help in studying the effects of known protein mutations in detail and potentially aid in identifying or predicting disease-causing mutations, the researchers say. Heart muscles are a form of striated muscles whose structure helps them perform the fast and continuous pumping movement that requires extreme efficiency. Their contraction and relaxation require energy and it is orchestrated by the interaction of a number of proteins. Genetic mutations causes them to pump either less blood or more blood than necessary.
“Such heart (muscle) mutations happen in roughly one in 500 people and the structure itself changes. Sometimes, this could lead to enlarged atria or ventricles and that makes the heart either hyper- or hypo-efficient,” says R Sowdhamini, associate professor, NCBS, who co-authored the research paper published in the scientific journal Bioinformatics and Biology Insights earlier this month. The paper's lead author, Margaret Sunitha, is a research student at Sowdhamini’s lab, which works on computational approaches to protein science. The other co-authors include James Spudich, a scientist at the Stanford University School of Medicine and John Mercer, visiting professor at the Bangalore-based Institute for Stem Cell Biology and Regenerative Medicine (inStem).
The heart muscle fibre consists of thin and thick filaments composed of actin and myosin, respectively. The actin is a multifunctional protein, while tropomyosin regulates actin mechanics to control muscle contraction, which is a cyclical event spread across three states of protein interaction — blocked, closed and open. The latter state represents the maximum myosin binding and force production.
The researchers integrated data from eight different sources, such as electromicroscopy and X-ray crystallography, to demonstrate the interaction of tropomyosin and actin in the ‘open’ form for the first time. The researchers also divided the sequence of interaction between tropomyosin and actin into seven periods and to study the impact of potential mutations in