The Leucine Zipper & Cancer

If each cell in the human body contains the same genetic information, why do they produce different proteins? Why, for instance, does the pancreas produce insulin while liver cells produce bile?

Although scientists have known the big-picture answer for several decades, they're still working out important details. Genes, made of DNA, carry the instructions for building proteins. But what activates the instructions? Since the late 1960s, researchers have known that certain proteins work like molecular switches, binding to DNA and switching on or silencing the gene's ability to synthesize a particular protein.

For the past three years, biophysical chemist Bruce Tidor has been studying one major family of these gene "switches." Proteins in this interesting family are formed when two separate proteins "zip" together to make a two-unit complex called a dimer. Because the "teeth" of the zipper holding the dimer together frequently are the amino-acid leucine, this structural motif is known as the "leucine zipper."

"Studies of the leucine zipper," says Tidor, a fellow at the Whitehead Institute for Biomedical Research in Cambridge, Mass., "provide basic information about the forces that hold proteins together and also contribute to better understanding of the molecular mechanisms underlying cancer." The leucine zipper, notes Tidor, appears to play a prominent role in the activity of two well-known oncogenes -- cancer-causing genes. Researchers have speculated that cancer may result when mutations in the leucine zipper cause abnormal dimers to form. Thus more detailed information about the structure of the leucine zipper could provide a foundation for designing highly specific anti-cancer drugs.

Tidor uses the CRAY C90 at Pittsburgh Supercomputing Center to find out how very small changes in protein structure can affect the how the protein functions. This kind of computer modeling is analogous to trying a new recipe without actually cooking the dish, and it can save years of laboratory time. His research has yielded new information about how two protein coils zip together to form the leucine zipper.

The two helices of the leucine zipper, shown here in top (left) and front (right) views, are outlined as yellow-striped ribbons. The ribbons gently wrap around each other, apparent in the top view. The stick figure represents the molecular structure -- oxygen (red), nitrogen (blue), hydrogen (white) and carbon (green). The dotted surface shows the area of the molecule that can come into contact with surrounding water. As seen in the top view, the surface shields the interface between the helices so that water is not able to penetrate into this area, where leucine and other hydrophobic amino acids form the "teeth" of the zipper.

Researchers: Bruce Tidor, Massachusetts Institute of Technology
Hardware: CRAY C-90
Software: CHARMM
Keywords: Leucine zipper, genes, protein, DNA, gene switches, dimer, oncogenes, cancer, hydrophobic, mutation, coils, salt bridges, site-specific mutagenesis, amino acids.

Related Material on the Web:
Projects in Scientific Computing, PSC's annual research report.

References, Acknowledgements & Credits