Biology:14-3-3 protein

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Short description: Family of conserved regulatory molecules
14-3-3
2bq0 14-3-3.png
Cartoon diagram of Human 14-3-3 protein beta PDB entry 2bq0 [1]
Identifiers
Symbol14-3-3
PfamPF00244
InterProIPR000308
SMART14_3_3
PROSITEPDOC00633
SCOP21a4o / SCOPe / SUPFAM

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 in cerebrospinal fluid may be a sign of Creutzfeldt–Jakob disease.[2]

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

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. Protists have at least one. Eukaryotes 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.[citation needed]

14-3-3 proteins are structurally similar to the Tetratrico Peptide Repeat (TPR) superfamily, which 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.[3]

14-3-3 binds to peptides. There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or threonine 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 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 recognition motifs[4]
Canonical 
R[^DE]{0,2}[^DEPG]([ST])(([FWYLMV].)
                        |([^PRIKGN]P)
                        |([^PRIKGN].{2,4}[VILMFWYP]))
C-terminal 
R[^DE]{0,2}[^DEPG]([ST])[^P]{0,1}$
Non-phos (ATP) 
IR[^P][^P]N[^P][^P]WR[^P]W[YFH][ITML][^P]Y[IVL]
All entrys are in regular expression format. Newlines are added in "or" cases for readability. Phosphorylation sites are in bold.

The motif sites are way more diverse than the patterns here suggest. For an example with a modern recognizer using an artificial neural network, see the cited article.[5]

Discovery and naming

14-3-3 proteins were initially found in brain tissue in 1967 and purified using chromatography and gel electrophoresis. 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.[6]

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.[7]

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.[8]

The eta (YWHAH) isoform is reported to be a biomarker (in synovial fluid) for rheumatoid arthritis.[9] 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). [10]

14-3-3 proteins bind to and sequester the transcriptional coregulators YAP/TAZ to the cytoplasm, inhibiting their function.

14-3-3 regulating cell-signalling

Human genes

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 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.[12]

References

  1. ↑ Yang, X.; Lee, W. H.; Sobott, F.; Papagrigoriou, E.; Robinson, C. V.; Grossmann, J. G.; Sundstrom, M.; Doyle, D. A. et al. (2006). "Structural basis for protein-protein interactions in the 14-3-3 protein family.". Proc. Natl. Acad. Sci. U.S.A. 103 (46): 17237–17242. doi:10.1073/pnas.0605779103. PMID 17085597. Bibcode: 2006PNAS..10317237Y. 
  2. ↑ "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. November 1999. doi:10.1128/CDLI.6.6.983-985.1999. PMID 10548598. 
  3. ↑ "14-3-3 proteins: a number of functions for a numbered protein". Science's STKE 2005 (296): re10. August 2005. doi:10.1126/stke.2962005re10. PMID 16091624. 
  4. ↑ "ELM search: "14-3-3"". http://elm.eu.org/combined_search?query=14-3-3. 
  5. ↑ "14-3-3-Pred: improved methods to predict 14-3-3-binding phosphopeptides". Bioinformatics 31 (14): 2276–83. July 2015. doi:10.1093/bioinformatics/btv133. PMID 25735772. 
  6. ↑ "14-3-3 proteins: a historic overview". Semin Cancer Biol 50 (6): 993–1010. 2006. doi:10.1023/A:1021261931561. PMID 16678438. 
  7. ↑ "Immunoglobulin class-switch DNA recombination: induction, targeting and beyond". Nat Rev Immunol 12 (7): 517–31. June 2012. doi:10.1038/nri3216. PMID 22728528. 
  8. ↑ "Regulation of the cellular DNA double-strand break response". Biochemistry and Cell Biology 85 (6): 663–74. December 2007. doi:10.1139/O07-135. PMID 18059525. 
  9. ↑ Kilani, R. T.; Maksymowych, W. P.; Aitken, A.; Boire, G.; St-Pierre, Y.; Li, Y.; Ghahary, A. (2007). "Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation". The Journal of Rheumatology 34 (8): 1650–1657. PMID 17611984. 
  10. ↑ "The role of 14-3-3 η as a biomarker in rheumatoid arthritis". Rheumatology and Immunology Research. 2 (2): 87–90. June 2021. doi:10.2478/rir-2021-0012. PMID 36465971. 
  11. ↑ "RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation". The Biochemical Journal 447 (1): 159–66. October 2012. doi:10.1042/BJ20120938. PMID 22827337. 
  12. ↑ "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): 6353–8. February 2002. doi:10.1074/jbc.M109637200. PMID 11744700. 

Further reading

  • FD Carlson, ed (1967). Physiological and Biochemical Aspects of Nervous Integration. Prentice-Hall, Inc., The Marine Biological Laboratory, Woods Hole, MA. pp. 343–359. 
  • "14-3-3 proteins--an update". Cell Research 15 (4): 228–36. April 2005. doi:10.1038/sj.cr.7290291. PMID 15857577. 
  • "14-3-3 proteins in neurodegeneration". Seminars in Cell & Developmental Biology 22 (7): 696–704. September 2011. doi:10.1016/j.semcdb.2011.08.005. PMID 21920445. 

External links



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