14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors. More than 200 signaling proteins have been reported as 14-3-3 ligands. Elevated amounts of 14-3-3 proteins are found in the cerebrospinal fluid of patients with Creutzfeldt–Jakob disease.
Properties
There are seven genes that encode seven distinct 14-3-3 proteins in most mammals and 13-15 genes in many higher plants, though typically in fungi they are present only in pairs. Protists have at least one. Eukaryotes can toleratethe loss of a single 14-3-3 gene if multiple genes are expressed, however deletion of all 14-3-3s results in death. 14-3-3 proteins are structurally similar to the Tetratrico Peptide Repeat superfamily, which generally have 9 or 10 alpha helices, and usually form homo- and/or hetero-dimer interactions along their amino-termini helices. These proteins contain a number of known common modification domains, including regions for divalent cation interaction, phosphorylation & acetylation, and proteolytic cleavage, among others established and predicted. 14-3-3 binds to peptides. There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or threonine residue, although binding to non-phosphorylated ligands has also been reported. This interaction occurs along a so-called binding groove or cleft that is amphipathic in nature. To date, the crystal structures of six classes of these proteins have been resolved and deposited in the public domain.
14-3-3 proteins play an isoform-specific role in class switch recombination. They are believed to interact with the protein Activation-Induced Deaminase in mediating class switchrecombination. Phosphorylation of Cdc25C by CDS1 and CHEK1 creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition. The eta isoform is reported to be a biomarker for rheumatoid arthritis.
