St. Jude Children's Research Hospital scientists have mapped the structural details of how p53 attaches to its regulatory protein, called BCL-xL, in the cell. The protein p53 is a key activator of the cell's protective machinery against genetic damage, such as the mutations that drive cancer cells' explosive growth.
The detailed understanding of how these two molecular puzzle pieces fit together will help scientists design drugs that release p53 in cancer cells, triggering their suicide, called apoptosis.
The findings appear in the current online journal Nature Structural & Molecular Biology. The research was led by co-corresponding authors Richard Kriwacki, Ph.D., a member of the St. Jude Structural Biology department, and Douglas Green, Ph.D., chair of the St. Jude Immunology department.
In guarding the cell against genetic damage, the p53 machinery functions both in the nucleus of the cell and in the cell's gel-like cytosol. When this machinery detects irreparable damage to the cell, p53 is unleashed to trigger apoptosis. In about half of all cancers, this machinery is rendered inoperable by mutation of p53, enabling cancer cells to proliferate despite their genetic malfunctions.
The protein BCL-xL is a central inhibitor of the p53 machinery, binding both p53 and other moleculescalled BH3 proteinsthat also drive apoptosis.
"The molecular details of how BCL-xl performs this dual inhibitory function were not understood," Kriwacki said. "Having those details has enabled us to determine exactly how BCL-xl can restrain or inhibit apoptosis through interactions with BH3-domain-containing proteins, as well as p53."
In their studies, the researchers used a structural analysis technique called NMR spectroscopy to map the 3-D structure of p53 binding to BCL-xL. Their experiments also revealed in detail how one region of the p53 protein, called the DNA-binding domain, serves double duty in the machinery. It
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St. Jude Children's Research Hospital