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Why Is 14-3-3 So Different from Other Family Members?

The 14-3-3 homodimer contains a unique binding surface (blue).

The 14-3-3 proteins are a family of proteins that perform a variety of roles in eukaryotic signal transduction. All 7 isoforms, except for 14-3-3, form a variety of homodimers and heterodimers and have overlapping roles in ligand binding. The 14-3-3 isoform, however, appears to play a specialized role in cellular response to DNA damage and in human oncogenesis. The protein also contains several short regions that differ in sequence from other 14-3-3 proteins. Erik W. Wilker and colleagues have now figured out what makes 14-3-3 so different by determining its crystal structure bound to a phosphopeptide ligand.

The researchers discovered that 14-3-3 preferentially forms homodimers and that unique stabilizing ring-ring and salt bridge interactions reinforce this interaction. Heterodimers of 14-3-3, on the other hand, are destabilized by electrostatic interactions. The phosphopeptide ligand interacts with 14-3-3 in a manner conserved throughout all isoforms, but the structure suggests that there is a second ligand binding site involved in 14-3-3-specific ligand discrimination. This site contains residues that are specific to 14-3-3. Mutation of these 14-3-3-specific residues to the corresponding sequence in other 14-3-3 proteins causes 14-3-3 to bind to Cdc25C, a molecule that normally binds to other 14-3-3 isoforms but not to 14-3-3.

FOOTNOTES

See referenced article, J. Biol. Chem. 2005, 280, 18891–18898

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