14-3-3 proteins are a family of conserved regulatory

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...

s that are expressed in all

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

cells. 14-3-3

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

s have the ability to bind a multitude of functionally diverse signaling proteins, including

kinase In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Ph ...

s, and

transmembrane receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...

s. More than 200 signaling proteins have been reported as 14-3-3 ligands. Elevated amounts of 14-3-3 proteins in

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

may be a sign of

Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes ...

Properties

Seven genes 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.

Protist A protist () is any eukaryotic organism (that is, an organism whose cells contain a cell nucleus) that is not an animal, plant, or fungus. While it is likely that protists share a common ancestor (the last eukaryotic common ancestor), the e ...

s have at least one.

Eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...

s can tolerate the loss of a single 14-3-3 gene if multiple genes are expressed, but deletion of all 14-3-3s (as experimentally determined in yeast) results in death. 14-3-3 proteins are structurally similar to the Tetratrico Peptide Repeat (TPR) superfamily, which generally have 9 or 10

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues earli ...

, 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 An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

interaction,

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opp ...

, 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 Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...

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 An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...

in nature. To date, the crystal structures of six classes of these proteins have been resolved and deposited in the public domain.

Discovery and naming

14-3-3 proteins were initially found in brain tissue in 1967 and purified using

chromatography In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system ( ...

and

gel electrophoresis Gel electrophoresis is a method for separation and analysis of biomacromolecules ( DNA, RNA, proteins, etc.) and their fragments, based on their size and charge. It is used in clinical chemistry to separate proteins by charge or size (IEF ...

. In bovine brain samples, 14-3-3 proteins were located in the 14th fraction eluting from a DEAE-cellulose column and in position 3.3 on a starch electrophoresis gel.

Function

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 M-phase inducer phosphatase 3 is an enzyme that in humans is encoded by the ''CDC25C'' gene. This gene is highly conserved during evolution and it plays a key role in the regulation of cell division. The encoded protein is a tyrosine phosphatase ...

CDS1 Phosphatidate cytidylyltransferase 1 is an enzyme that in humans is encoded by the ''CDS1'' gene. Function Breakdown products of phosphoinositides are ubiquitous second messengers that function downstream of many G protein-coupled receptors ...

and

CHEK1 Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the ''CHEK1'' gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Ch ...

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 (

YWHAH 14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene. Function This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate si ...

) isoform is reported to be a biomarker (in

synovial fluid Synovial fluid, also called synovia, elp 1/sup> is a viscous, non-Newtonian fluid found in the cavities of synovial joints. With its egg white–like consistency, the principal role of synovial fluid is to reduce friction between the articul ...

) for

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and ...

. In a systematic review, 14-3-3η has been described as a welcome addition to the rheumatology field. The authors indicate that the serum based 14-3-η marker is additive to the armamentarium of existing tools available to clinicians, and that there is adequate clinical evidence to support its clinical benefits in the management of patients diagnosed with rheumatoid arthritis (RA). 14-3-3 proteins bind to and sequester the transcriptional coregulators YAP/

TAZ Taz or TAZ may refer to: Geography * Taz (river), a river in western Siberia, Russia * Taz Estuary, the estuary of the river Taz in Russia People * Taz people, an ethnic group in Russia ** Taz language, a form of Northeastern Mandarin spoken ...

to the cytoplasm, inhibiting their function.

14-3-3 regulating cell-signalling

* Raf-1 * Bad – see

Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death ( apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosi ...

* Bax * Cdc25 * Akt * SOS1 – see RSK

Human genes

* – " 14-3-3 beta" * – "14-3-3 epsilon" * – "

14-3-3 gamma 14-3-3 protein gamma is a protein that in humans is encoded by the ''YWHAG'' gene. This gene product belongs to the 14-3-3 protein family which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved pro ...

" * – "

14-3-3 eta 14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene. Function This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate sig ...

" * – " 14-3-3 tau" * – "14-3-3 zeta" * or – "14-3-3 sigma" (Stratifin) The 14-3-3 proteins alpha and delta (YWHAA and YWHAD) are phosphorylated forms of YWHAB and YWHAZ, respectively.

In plants

The presence of large gene families of 14-3-3 proteins in the

Viridiplantae Viridiplantae (literally "green plants") are a clade of eukaryotic organisms that comprise approximately 450,000–500,000 species and play important roles in both terrestrial and aquatic ecosystems. They are made up of the green algae, which a ...

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.

References

External links

* * * *
Three-dimensional structure of 14-3-3 Protein Theta (Human) complexed with a peptide in the PDB.

{{Adaptor proteins Programmed cell death Protein families 14-3-3 proteins