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Key fat and cholesterol cell regulator identified, promising target

ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences, which partially supported the research. "This work highlights the value of model organisms in helping us understand cellular processes that impact human health."

The research team also showed that removal of ARC105 in human cells by RNAi also negatively affects the same key SREBP target gene as identified in C. elegans. This suggests that the molecular switch is evolutionarily conserved (and therefore likely physiologically important).

Exhaustive biochemical detective work performed by the Nr group together with the group of Gerhard Wagner, PhD, HMS professor in the Department of Biological Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105 interact. They found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX.

The researchers analyzed the amino acid sequence of the ARC105 protein, testing many different sections using NMR spectroscopy to eventually find the KIX area--just one tenth the area of the larger ARC105 protein--that specifically binds to SREBP. This specific interaction between SREBP and ARC105 might be a target for small molecule drugs, according to Dr. Wagner.

"While RNAi completely knocks out a protein including its other functions, perhaps not related to fat metabolism, a small molecule is a more subtle tool that could eliminate one protein-to-protein interaction," says Dr. Wagner. Finding a molecule that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search for inhibitors to fit the grooved KIX site looks much more promising.

The team is already initiating high-throughput screening at Harvard Medical School's Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the KIX site.

"Of course there are numerous hu
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Contact: John Lacey
public_affairs@hms.harvard.edu
617-432-0442
Harvard Medical School
2-Aug-2006


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