2 Institute of Physiology, Academy of Sciences of the Czech Republic, CZ-14220 Praha 4, Czech Republic
14-3-3 proteins were the first signaling proteins to be identified as discrete phosphoserine/phosphothreonine binding molecules. These proteins play an important role in the regulation of signal transduction, apoptosis, cell cycle control, and nutrient-sensing pathways [1,2]. The 14-3-3 proteins are a conserved family of acidic proteins (molecular mass ranging from 27 to 32 kDa) present in high abundance in all eukaryotic organisms studied so far. Many organisms express multiple isoforms; for example, in mammals seven isoforms have been identified. All 14-3-3 isoforms can form stable homo and hetero-dimers. Though 14-3-3 proteins perform different functions for different ligands, general mechanisms of 14-3-3 action include changes in activity of bound enzymes, control in sub-cellular localization of 14-3-3 bound proteins, and alterations in protein-protein interactions of bound ligands with other proteins.
Crystal structures of human 14-3-3 zeta and tau isoforms, and structures of 14-3-3zeta bound to various peptides representing 14-3-3 binding motifs provided first structural insight into understanding of the biological function of 14-3-3 proteins [3,4]. These structures illustrate the conserved fold of the 14-3-3 proteins, where each monomer is composed of nine antiparallel a-helices, and two monomers form cup-shaped dimers with a large deep channel in the center running the length of the dimer. The walls of the channel contain amphipathic grooves that are ~30 Å long, and residues lining the grooves are mostly conserved among the different isoforms. Phosphoserine-containing peptides were observed to bind in an extended conformation within these grooves. Recently, the structure of 14-3-3zeta bound to an enzyme serotonin N-acetyltransferase in complex with a bisubstrate analog, was solved . This structure allowed to describe how 14-3-3 interacts with an enzymatically active protein – 14-3-3 stabilizes the conformation of an adjacent region in the enzyme, causing enhanced substrate binding and product formation.
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