14-3-3 protein
Encyclopedia
14-3-3 proteins are a family of conserved regulatory molecule
s expressed in all eukaryotic
cells. 14-3-3 protein
s have the ability to bind a multitude of functionally diverse signaling proteins
, including kinase
s, phosphatase
s, and transmembrane receptors. More than 100 signaling proteins have been reported as 14-3-3 ligands.
The name 14-3-3 refers to the particular elution and migration pattern of these proteins on DEAE
-cellulose chromatography and starch-gel electrophoresis
. The 14-3-3 proteins eluted in the 14th fraction of bovine brain homogenate and were found on positions 3.3 of subsequent electrophoresis by Moore and Perez (1967).
Elevated amounts of 14-3-3 proteins are found in the cerebrospinal fluid
of patients with Creutzfeldt-Jakob disease
.
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.
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 an 'x' can be several, but not all of the 20 amino acids and 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.
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.
Phosphorylation of Cdc25C by CDS1 and CHK1 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.
- "14-3-3 gamma" - "14-3-3 eta" - "14-3-3 tau" - "14-3-3 zeta"
- "14-3-3 sigma"
A phylogenetic analysis of 27 plant species clustered the 14-3-3 proteins into four groups.
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s expressed in all eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cells. 14-3-3 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s have the ability to bind a multitude of functionally diverse signaling proteins
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
, including kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s, phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
s, and transmembrane receptors. More than 100 signaling proteins have been reported as 14-3-3 ligands.
The name 14-3-3 refers to the particular elution and migration pattern of these proteins on DEAE
DEAE
Diethylaminoethyl cellulose is a positively charged resin used in ion exchange chromatography, a type of column chromatography, used in protein and nucleic acid purification/separation...
-cellulose chromatography and starch-gel electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
. The 14-3-3 proteins eluted in the 14th fraction of bovine brain homogenate and were found on positions 3.3 of subsequent electrophoresis by Moore and Perez (1967).
Elevated amounts of 14-3-3 proteins are found in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
of patients with Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease
Creutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
.
Properties of 14-3-3 proteins
There are seven genes that encode 14-3-3s 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 tolerate the loss of an 14-3-3 isoform if multiple isoforms are present, however deletion of all 14-3-3s (as experimentally determined in yeast) results in death.14-3-3 proteins can be considered evolved members of the Tetratrico Peptide Repeat (TPR) superfamily, generally have 9 or 10 alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
, 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
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
& acetylation
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
, and proteolytic cleavage, among others established and predicted.
There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
residue; Mode 1 is R[SFYW]XpSXP & Mode 2 RX[SYFWTQAD]Xp(S/T)X[PLM] (where an 'x' can be several, but not all of the 20 amino acids and 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.
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
Activation-Induced (Cytidine) Deaminase
Activation-induced deaminase is a 24 kDa enzyme that creates deliberate mutations in DNA.AID removes the amino group from a cytidine base, turning it into a uridine...
in mediating class switch recombination.
Phosphorylation of Cdc25C by CDS1 and CHK1 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.
14-3-3 regulating cell-signalling
- Raf-1C-RafRAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
- BadBcl-2-associated death promoterThe Bcl-2-associated death promoter protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family...
- see Bcl-2Bcl-2Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in... - Bax
- Cdc25Cdc25Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...
Human Genes
- "14-3-3 alpha" - "14-3-3 beta" - "14-3-3 delta" - "14-3-3 epsilon"YWHAE
14-3-3 protein epsilon is a protein that in humans is encoded by the YWHAE gene.-Interactions:YWHAE has been shown to interact with CDC25B, Insulin-like growth factor 1 receptor, NGFRAP1, TGF beta 1, HERG, C-Raf, NDEL1, HDAC4, IRS1 and MAP3K3....
- "14-3-3 gamma" - "14-3-3 eta" - "14-3-3 tau" - "14-3-3 zeta"
YWHAZ
14-3-3 protein zeta/delta is a protein that in humans is encoded by the YWHAZ gene.-Interactions:YWHAZ has been shown to interact with TSC2, LIMK1, CDC25B, AKT1, BCAR1, Interleukin-9 receptor, C-Raf, HMGN1, Vimentin, Tau protein, Protein kinase Mζ, GP1BB, GP1BA, TNFAIP3, Bcl-2-associated death...
- "14-3-3 sigma"
14-3-3 in plants
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.