St. Jude Children's Research Hospital investigators have gained new insight into how the cell's vast array of proteins would instantly be reduced to a confusion of lethally malfunctioning molecules without a system for proteins to "accessorize" in order to regulate their function.
Just as eyeglasses improve vision, a coat provides warmth or an umbrella wards off rain, cells use a set of proteins called ubiquitin-like proteins (UBLs) as accessories that adapt their function as needed in the cell. Now St. Jude scientists have discovered how the function of a protein called cullin-RING changes when it wears the UBL accessory called NEDD8.
The researcher's findings, published in the Sept. 19, 2008, issue of the journal "Cell," reveal that NEDD8 changes the shape of cullin-RING to activate it to perform its function. The researchers found that when NEDD8 attaches, it transforms cullin-RING into a kind of molecular valet that can then attach a different accessory (ubiquitin) onto other proteins to foster the myriad of biochemical reactions that enable life.
"The ubiquitination machinery is critical for the cell's proteins to be able to function as necessary in a given environment. One of the major functions of ubiquitin is to mark a protein for disposal when its job is done," said Brenda Schulman, Ph.D., associate member in the St. Jude Structural Biology and Genetics and Tumor Cell Biology departments and Howard Hughes Medical Institute (HHMI) investigator. "Understanding ubiquitination can give us important knowledge about such biological processes as cell division, embryonic development and immune function." Schulman is the paper's senior author.
"Basic insights into ubiquitination could ultimately have clinical application, because defects in the machinery have been implicated in cancers, neurodegenerative disorders and some viral infections," said David Duda, Ph.D., the paper's co-first author and HHMI research specialist in
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St. Jude Children's Research Hospital