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April 17, 2003

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Structure Reveals Keys to Important Gene Regulator

A team of researchers from Johns Hopkins and the University of Colorado has discovered a chink in the structure of a gene-controlling protein critical in regulating the growth and death of immune, brain and muscle cells, they report in the April 17 issue of Nature.

The "chink" is a groove in the top of the protein, called MEF2, that holds onto other proteins like a bun holds a hotdog. Since binding those proteins lets MEF2 control expression of a host of genes, blocking the "bun" may reveal ways to treat a number of common conditions. Already, MEF2 has been implicated in general inflammation and heart hypertrophy -- an enlarging of the heart that occurs as its ability to pump blood fails.

"Now that we have the structure of MEF2, we can work toward finding ways to block it using molecules that could become potential drugs," says Jun Liu, Ph.D., professor of pharmacology and neuroscience in the Institute for Basic Biomedical Sciences at Johns Hopkins. "We don't know what effect blocking MEF2 would have, but we now know it's possible to try."

The prevalence of MEF2 in many different cell types may limit its usefulness as a target of drugs, notes Liu. However, with the structural information they now have, it's possible to begin looking for blocking agents to test that idea and to find "downstream" genes that may be even better targets for therapeutic strategies, he says.

In addition to regulating some genes that control muscle cells, MEF2 also influences genes critical to the fate of brain and immune cells. Since 1999, Liu's laboratory has been studying MEF2 and the proteins that help it control the activity of certain genes in response to cellular levels of calcium.

"We've been able to establish the logic of which players are involved with MEF2, but didn't know if our explanations for their involvement made sense structurally," says Liu. "Now we know that the structure does support our earlier observations."

MEF2 controls gene activity by sitting on a region of DNA that is essentially the starting line for a gene. A select group of helper proteins then bind to the top of MEF2. When levels of calcium rise in the cell, proteins that normally help silence genes are replaced by others that help activate them (particularly calcium-binding proteins like calmodulin).

The structure, determined by colleagues at the University of Colorado, shows that the required helper proteins are bound in a groove in the top of MEF2. Johns Hopkins postdoctoral fellow Fan Pan, Ph.D., altered some of the building blocks in that groove, affecting the protein's ability to bind its normal helpers. The findings help explain how MEF2 can be found in such different kinds of cells, say the researchers.

"Different types of cells have a different subset of four very similar versions of MEF2, each of which binds the same genes but different helper proteins," says Liu. "Now we know that subtle differences in the protein-binding groove give each MEF2 its specificity, preventing a cell from carrying out inappropriate instructions. You don't want a muscle cell following instructions that should be limited to an immune cell, for example."

Authors on the paper are Liu, Pan, and Hong-Duk Youn of Johns Hopkins, and Aidong Han, James Stroud, and Lin Chen of the University of Colorado at Boulder. The Johns Hopkins researchers were funded by the National Institutes of Health.

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