Member database | CATH-Gene3D |
CATH-Gene3D type | homologous superfamily |
Description Imported from IPR036815
The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells
[2, 1]. These are structurally similar phospho-binding proteins that regulate multiple signaling pathways
[3]. There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.
The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.
References Imported from IPR036815
1.How do 14-3-3 proteins work?-- Gatekeeper phosphorylation and the molecular anvil hypothesis. Yaffe MB. FEBS Lett. 513, 53-7, (2002). View articlePMID: 11911880
2.Distinct forms of the protein kinase-dependent activator of tyrosine and tryptophan hydroxylases. Isobe T, Ichimura T, Sunaya T, Okuyama T, Takahashi N, Kuwano R, Takahashi Y. J. Mol. Biol. 217, 125-32, (1991). View articlePMID: 1671102
Integrated to
External Links
Representative structure
4dhr: Small-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening