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Apr 4, 2007

Novel Mechanism of Action Discovered for Ubiquitin Ligases

  • A team of scientists have determined how a plant hormone, auxin, interacts with the TIR1 receptor. They report that their findings may have implications for the treatment of human disease since TIR1 is part of the ubiquitin ligase family, which is known to influence cancerous cell division in humans.

    "A number of human disorders, including Parkinson's disease and colon and breast cancers, are caused by defective interactions between ubiquitin ligases and their substrate polypeptides," says Ning Zheng, pharmacologist at the University of Washington School of Medicine. “What the plant hormone tells us is that it might be possible to rescue these interactions using small molecules.”

    In the study, the scientists extracted and purified TIR1 from the common plant model Arabidopsis. By x-raying crystals of the protein, they determined the enzyme's 3-D structure. The team then soaked the crystal in a solution containing auxin and repeated the x-ray treatment to determine where the auxin had bound. Finally, a peptide was added that TIR1 is known to bind  and modify.

    Up until now, it was believed the ubiquitin ligases could only be controlled through protein-protein interactions. The investigators learned, however, that auxin improves the ability of TIR1 to bind its peptide target. Because the architecture of TIR1 is highly conserved among other ubiquitin ligases, including those in human cells, the scientists expect other ubiquitin ligases may be affected by small molecules like auxin.

    The study appeared in this week's issue of Nature. It was performed by researchers from the University of Washington School of Medicine, Indiana University Bloomington, and the University of Cambridge. 


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