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104  structures 551  species 1  interaction 2097  sequences 15  architectures

Family: 14-3-3 (PF00244)

Summary: 14-3-3 protein

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This is the Wikipedia entry entitled "14-3-3 protein". More...

14-3-3 protein Edit Wikipedia article

14-3-3
PDB 1ib1 EBI.jpg
Crystal structure of the 14-3-3 zeta:serotonin N-acetyltransferase complex.[1]
Identifiers
Symbol 14-3-3
Pfam PF00244
InterPro IPR000308
SMART 14_3_3
PROSITE PDOC00633
SCOP 1a4o
SUPERFAMILY 1a4o

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.

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.[2]

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

Properties of 14-3-3 proteins[edit]

There are seven genes that encode seven distinct 14-3-3 isoforms 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 a single 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, 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 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.

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.[3]

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.

14-3-3 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.[4]

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 (2005). "14-3-3 proteins--an update". Cell Res. 15 (4): 228–236. doi:10.1038/sj.cr.7290291. PMID 15857577. 

References[edit]

  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 et al. (November 1999). "Increased levels of epsilon and gamma isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt-Jakob disease". Clin. Diagn. Lab. Immunol. 6 (6): 983–5. PMC 95810. PMID 10548598. 
  3. ^ Cann KL, Hicks GG (2007). "Regulation of the cellular DNA double-strand break response.". Biochem Cell Biol 85 (6): 663–74. doi:10.1139/O07-135. PMID 18059525. 
  4. ^ Thomas P. Jahn, Alexander Schulz, Jan Taipalensuu & Michael Gjedde Palmgren (February 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. 

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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Literature references

  1. Xiao B, Smerdon SJ, Jones DH, Dodson GG, Soneji Y, Aitken A, Gamblin SJ; , Nature 1995;376:188-191.: Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. PUBMED:7603573 EPMC:7603573

  2. Liu D, Bienkowska J, Petosa C, Collier RJ, Fu H, Liddington R; , Nature 1995;376:191-194.: Crystal structure of the zeta isoform of the 14-3-3 protein. PUBMED:7603574 EPMC:7603574

  3. Muslin AJ, Tanner JW, Allen PM, Shaw AS; , Cell 1996;84:889-897.: Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. PUBMED:8601312 EPMC:8601312

  4. Ichimura T, Ito M, Itagaki C, Takahashi M, Horigome T, Omata S, Ohno S, Isobe T , FEBS Lett 1997;413:273-276.: The 14-3-3 protein binds its target proteins with a common site located towards the C-terminus. PUBMED:9280296 EPMC:9280296

  5. Wang W, Shakes DC , J Mol Evol 1996;43:384-398.: Molecular evolution of the 14-3-3 protein family. PUBMED:8798343 EPMC:8798343

  6. Jin DY, Lyu MS, Kozak CA, Jeang KT , Nature 1996;382:308-308.: Function of 14-3-3 proteins. PUBMED:8684458 EPMC:8684458

  7. Ferl RJ, Manak MS, Reyes MF; , Genome Biol 2002;3:REVIEWS3010.: The 14-3-3s. PUBMED:12184815 EPMC:12184815


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR023410

The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimeric within all eukaryotic cells [PUBMED:1671102, PUBMED:11911880]. 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.

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). 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.

This entry represents the structural domain found in 14-3-3 proteins.

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Representative proteomes NCBI
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RP15
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RP35
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RP55
(682)
RP75
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  Seed
(85)
Full
(2097)
Representative proteomes NCBI
(1919)
Meta
(23)
RP15
(308)
RP35
(472)
RP55
(682)
RP75
(918)
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Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 85
Number in full: 2097
Average length of the domain: 196.20 aa
Average identity of full alignment: 57 %
Average coverage of the sequence by the domain: 83.35 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.4 21.4
Trusted cut-off 21.4 22.0
Noise cut-off 21.3 21.3
Model length: 236
Family (HMM) version: 15
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14-3-3

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the 14-3-3 domain has been found. There are 104 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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