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MSKCC researchers uncover structure of key protein complex in cells

ells.

Ubiquitin acts as a chemical tattoo that marks damaged or obsolete proteins for destruction by a protein complex in the cell called the proteasome. Cancer researchers became particularly interested in ubiquitin with the discovery that it tags and regulates many cell-cycle proteins for destruction. One of these proteins is p53, a "tumor suppressor" that, when working properly, can prevent runaway cell growth. In normal cells ubiquitin marks p53 for destruction. But in cells with damaged DNA, p53 evades getting tagged with ubiquitin to allow its accumulation, thus enabling the p53 suppressor protein to stifle the formation of tumors.

Three scientists -- two Israelis and an American -- were awarded the 2004 Nobel Prize in Chemistry for their work showing that ubiquitin marks other proteins for destruction.

SUMO-1 does not appear to label other proteins for destruction. It instead appears to alter their function in different ways, perhaps even by preventing ubiquitin tagging. Still, there are enough similarities between conjugation of SUMO and ubiquitin that the latest findings could help researchers understand both. "The structural network has revealed a mechanism that may be important in the regulation process in the SUMO and ubiquitin pathways; pathways that need to operate properly for normal cell division," Dr. Lima said.

The complex described by Drs. Lima and Reverter includes SUMO-1, a substrate, and two other proteins, called E2 and E3. E2 links SUMO to target molecules, while E3 is a kind of chemical marriage broker, bringing targets close enough to SUMO to facilitate binding.

"E3 activities are somewhat mysterious," Dr. Lima said. "They stimulate conjugation, but how they do so remains unclear. A major advance in this study was the development of quantitative assays that allowed us to develop a more sophisticated model for E3 activity," Dr. Lima said. "This model has broad implications for the function of E3s in al
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Source:Memorial Sloan-Kettering Cancer Center


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