U. of Colorado researchers solve molecular structure involved with heart disease
A group of researchers led by the University of Colorado at Boulder have solved the crystal structure of a molecule switch that can trigger heart disease and cancer, paving the way for future drug designs to mitigate these diseases.
The key component of the switch is a protein called MEF2 that binds to the DNA and is involved in muscle cell, T cell and nerve cell development. In cases involving human hearts, it can lower gene activity that causes enlarged hearts, known as hypertrophic cardiomyopathy, said Assistant Professor Lin Chen of CU-Boulders chemistry and biochemistry department who is leading the study.
MEF2 works in part by recruiting proteins known as histone deacetylases, or HDACs, that can modify DNA structure to suppress specific gene expression. MEF2 does so by either binding directly to HDACs or to an adaptor protein known as Cabin1 that in turn binds to HDACs.
Chen and his team recently determined the crystal structure of MEF2 that is bound to the molecule Cabin1 on DNA. Their studies revealed for the first time the detailed mechanisms by which MEF2 suppresses genes inside cells.
“The structure not only showed us how genes are properly silenced into a quiescent state by MEF2 and its associated molecules,” said Chen, “but more importantly, it also suggested potential mechanisms by which MEF2 activates gene expression when cells are stimulated, especially when cells are inappropriately activated during hypertrophic responses in ones heart.”
A paper on the subject will be published in the April 17 issue of Nature. The first author is Aidong Han, a postdoctoral fellow in the Chen lab. Other authors include James Stroud, a CU graduate student in the Chen lab, and Fan Pan, Hong-Duk Youn and Jun O. Liu from Johns Hopkins University in Baltimore.
MEF2 and HDACs have drawn much attention because of their medical relevance, playing a key role in heart hypertrophy, which is often a response to other heart diseases and eventually turns into heart failure, said Chen. In the Western World, cardiovascular diseases account for about 43 percent of human deaths and for about 50 percent of all human hospitalizations.
The function of HDACs also is the focus of intensive medical research, said Chen. Scientists have shown that inhibitors of HDACs can halt the proliferation of tumor cells and cause them to die.
A number of HDAC inhibitors now are in clinical trials as anti-cancer drugs, he said, and there are continued efforts to search for more specific and less toxic blockers of HDACs. “The picture we have now by which HDACs are recruited to DNA will undoubtedly help this endeavor,” he said.
“The structure reported by our lab is exciting because it suggests potential strategies for development of drugs to block the activity of HDACs and prevent MEF2 from activating genes in diseased cells,” said Chen. “These drugs may help patients with heart disease and hopefully some cancers, benefiting human health enormously.”
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