14-3-3 protein

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
PDB 1ib1 EBI.jpg
Crystal structure of the 14-3-3 zeta:serotonin N-acetyltransferase complex.[1]

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.[2]

Molecular structure of a 14-3-3 protein dimer bound to a peptide.


There are seven genes that encode seven distinct 14-3-3 proteins in most mammals (See Human genes below) 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 tolerate the loss of a single 14-3-3 gene if multiple genes are expressed, however deletion of all 14-3-3s (as experimentally determined in yeast) results in death.[citation needed]

14-3-3 proteins can be considered evolved members of the Tetratrico Peptide Repeat (TPR) superfamily, 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.[citation needed]

There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or threonine residue; Mode 1 is R[SFYW]XpSXP & Mode 2 RX[SYFWTQAD]Xp(S/T)X[PLM] (where letters like S,F... except "X" indicate an amino acid; an "X" can be several, but not any of the 20 amino acids; a lower case 'p' indicates the site of phosphorylation) but also binding to non-phosphorylated ligands has 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.[citation needed]


14-3-3 proteins play an isoform-specific role in class switch recombination. They are believed to interact with the protein Activation-Induced (Cytidine) Deaminase in mediating class switch recombination.[citation needed]

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.[3]

The eta isoform is reported to be a biomarker (in synovial fluid) for rheumatoid arthritis.[4]

14-3-3 regulating cell-signalling[edit]

Human genes[edit]

The 14-3-3 proteins alpha and delta (YWHAA and YWHAD) were found to be equivalent to YWHAB and YWHAZ, respectively, in that both alpha and delta forms are phosphorylated proteins.

In plants[edit]

Presence of large gene families of 14-3-3 proteins in the Viridiplantae kingdom reflects their essential role in plant physiology. A phylogenetic analysis of 27 plant species clustered the 14-3-3 proteins into four groups.

14-3-3 proteins activate the auto-inhibited plasma membrane P-type H+ ATPases. They bind the ATPases' C-terminus at a conserved threonine.[6]


  1. ^ T. Obsil; R. Ghirlando; D. C. Klein; S. Ganguly & F. Dyda (April 2001). "Crystal structure of the 14-3-3zeta:serotonin N-acetyltransferase complex. a role for scaffolding in enzyme regulation". Cell. 105 (2): 257–267. doi:10.1016/S0092-8674(01)00316-6. PMID 11336675.
  2. ^ Takahashi H, Iwata T, Kitagawa Y, Takahashi RH, Sato Y, Wakabayashi H, Takashima M, Kido H, Nagashima K, Kenney K, Gibbs CJ, Kurata T (Nov 1999). "Increased levels of epsilon and gamma isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt–Jakob disease". Clinical and Diagnostic Laboratory Immunology. 6 (6): 983–5. PMC 95810. PMID 10548598.
  3. ^ Cann KL, Hicks GG (Dec 2007). "Regulation of the cellular DNA double-strand break response". Biochemistry and Cell Biology. 85 (6): 663–74. doi:10.1139/O07-135. PMID 18059525.
  4. ^ Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation.
  5. ^ Saha, Madhurima; Carriere, Audrey; Cheerathodi, Mujeeburahiman; Zhang, Xiaocui; Lavoie, Geneviève; Rush, John; Roux, Philippe; Ballif, Bryan (2012). "RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation". Biochemical Journal. 447: 159–66. doi:10.1042/BJ20120938. PMC 4198020. PMID 22827337.
  6. ^ Jahn TP, Schulz A, Taipalensuu J, Palmgren MG (Feb 2002). "Post-translational modification of plant plasma membrane H(+)-ATPase as a requirement for functional complementation of a yeast transport mutant". The Journal of Biological Chemistry. 277 (8): 6353–6358. doi:10.1074/jbc.M109637200. PMID 11744700.

Further reading[edit]

  • Moore BW, Perez VJ (1967). FD Carlson (ed.). Physiological and Biochemical Aspects of Nervous Integration. Prentice-Hall, Inc., The Marine Biological Laboratory, Woods Hole, MA. pp. 343–359.
  • Mhawech P (Apr 2005). "14-3-3 proteins--an update". Cell Research. 15 (4): 228–236. doi:10.1038/sj.cr.7290291. PMID 15857577.
  • Steinacker P, Aitken A, Otto M (Sep 2011). "14-3-3 proteins in neurodegeneration". Seminars in Cell & Developmental Biology. 22 (7): 696–704. doi:10.1016/j.semcdb.2011.08.005. PMID 21920445.

External links[edit]