Alzheimer's disease

Clearest view yet of complex tied to cancer

BROWN (US) — Scientists have determined the structure of an enzyme complex that regulates vital cell functions.

Disregulation of such complexes is associated with diseases such as cancer and Alzheimer’s. The findings give drug developers a specific and unique new target to consider in their efforts to find new treatments.

“Disregulation always leads to disease,” says Wolfgang Peti, associate professor of medicine and chemistry at Brown University. “To make better drugs, what we want to do is look for individual things that are different between different complexes. The problem is we didn’t know where those non-common spots are. We didn’t have the structures that tell us the story. We were the first to get one of those structures.”


While not a household name, p38alpha:HePTP matters in millions of households around the world and is a member of the MAP kinase family that includes enzymes that regulate cell functions such as growth and inflammation. Diseases that correlate with disruptions to MAP kinase signaling include Alzheimer’s disease, rheumatoid arthritis, and cancer.

To determine the structure, researchers combined techniques including nuclear magnetic resonance spectroscopy and small-angle X-ray scattering, using the National Synchrotron Light Source at Brookhaven National Laboratory.

The result was the clearest picture yet of a MAP kinase complex, which turns out to measure a mere 108 Angstroms (tenths of billionths of a meter) long by 30 Angstroms wide. The resolution of the resulting model is on the scale of individual atoms.

To elucidate the model, the researchers probed the complex to discover areas where p38alpha binds to different HePTP-derived peptides and found a specific area called “KIS” that is responsible for how the p38alpha:HePTP complex forms in its unique way.

“That really showed there are these areas outside the common sites that are likely unique between different complexes,” Peti says.

The next step is to learn more about KIS and the role it could ultimately play in disregulation and disease. In the paper, published online in Nature Chemical Biology, the authors expressed optimism that their new-found knowledge will have clinical relevance.

“These results provide novel insights into the molecular interactions that regulate the strength and duration of MAP kinase signaling and, in turn, provide novel avenues for therapeutic interventions of MAP kinase-related diseases.”

The American Cancer Society funded the research.

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