14-3-3 protein

Last updated
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
Pfam PF00244
InterPro IPR000308
SMART 14_3_3
PROSITE PDOC00633
SCOP2 1a4o / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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.

Contents

Elevated amounts of 14-3-3 protein in cerebrospinal fluid are usually a sign of rapid neurodegeneration; a common indicator of Creutzfeldt–Jakob disease. [2]

Molecular structure of a 14-3-3 protein dimer bound to a peptide. 14-3-3dimer.png
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 14-3-3η 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.[ citation needed ]

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.[ citation needed ]

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.[ citation needed ]

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]

Related Research Articles

<span class="mw-page-title-main">SH3 domain</span> Small protein domain found in some kinases and GTPases

The SRC Homology 3 Domain is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src. It has also been identified in several other protein families such as: PI3 Kinase, Ras GTPase-activating protein, CDC24 and cdc25. SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton, the Ras protein, and the Src kinase and many others. The SH3 proteins interact with adaptor proteins and tyrosine kinases. Interacting with tyrosine kinases, SH3 proteins usually bind far away from the active site. Approximately 300 SH3 domains are found in proteins encoded in the human genome. In addition to that, the SH3 domain was responsible for controlling protein-protein interactions in the signal transduction pathways and regulating the interactions of proteins involved in the cytoplasmic signaling.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.

c-Raf Mammalian protein found in Homo sapiens

RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases. C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.

<span class="mw-page-title-main">HslVU</span> Class of bacterial heat shock proteins

The heat shock proteins HslV and HslU are expressed in many bacteria such as E. coli in response to cell stress. The hslV protein is a protease and the hslU protein is an ATPase; the two form a symmetric assembly of four stacked rings, consisting of an hslV dodecamer bound to an hslU hexamer, with a central pore in which the protease and ATPase active sites reside. The hslV protein degrades unneeded or damaged proteins only when in complex with the hslU protein in the ATP-bound state. HslV is thought to resemble the hypothetical ancestor of the proteasome, a large protein complex specialized for regulated degradation of unneeded proteins in eukaryotes, many archaea, and a few bacteria. HslV bears high similarity to core subunits of proteasomes.

<span class="mw-page-title-main">ETS1</span> Protein-coding gene in the species Homo sapiens

Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.

<span class="mw-page-title-main">YWHAH</span> Protein-coding gene in the species Homo sapiens

14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the YWHAH gene.

<span class="mw-page-title-main">PABPC1</span> Protein-coding gene in the species Homo sapiens

Polyadenylate-binding protein 1 is a protein that in humans is encoded by the PABPC1 gene. The protein PABP1 binds mRNA and facilitates a variety of functions such as transport into and out of the nucleus, degradation, translation, and stability. There are two separate PABP1 proteins, one which is located in the nucleus (PABPN1) and the other which is found in the cytoplasm (PABPC1). The location of PABP1 affects the role of that protein and its function with RNA.

<span class="mw-page-title-main">YWHAB</span> Protein-coding gene in the species Homo sapiens

14-3-3 protein beta/alpha is a protein that in humans is encoded by the YWHAB gene.

<span class="mw-page-title-main">Eukaryotic translation initiation factor 4 gamma 1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4 gamma 1 is a protein that in humans is encoded by the EIF4G1 gene.

<span class="mw-page-title-main">USF1</span> Protein-coding gene in the species Homo sapiens

Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.

<span class="mw-page-title-main">MAP2K7</span> Protein-coding gene in the species Homo sapiens

Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.

<span class="mw-page-title-main">SGK3</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the SGK3 gene.

<span class="mw-page-title-main">EIF4A1</span> Protein coding gene in Humans

Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.

<span class="mw-page-title-main">RPTOR</span> Protein-coding gene in humans

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

<span class="mw-page-title-main">Cdc6</span> Protein in eukaryotic cells

Cdc6, or cell division cycle 6, is a protein in eukaryotic cells. It is mainly studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading minichromosome maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it is a member of the family of AAA+ ATPases and highly related to ORC1; both are the same protein in archaea.

The Walker A and Walker B motifs are protein sequence motifs, known to have highly conserved three-dimensional structures. These were first reported in ATP-binding proteins by Walker and co-workers in 1982.

<span class="mw-page-title-main">WW domain</span>

The WW domain is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be repeated up to four times in some proteins. Apart from binding preferentially to proteins that are proline-rich, with particular proline-motifs, [AP]-P-P-[AP]-Y, some WW domains bind to phosphoserine- and phosphothreonine-containing motifs.

WH1 domains, also known as EVH1 domains, are evolutionary conserved protein domains found on WASP (VASP) proteins, which are often involved in actin polymerization.

<span class="mw-page-title-main">Calponin 1</span> Protein found in humans

Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.

References

  1. ↑ Yang, X.; Lee, W. H.; Sobott, F.; Papagrigoriou, E.; Robinson, C. V.; Grossmann, J. G.; Sundstrom, M.; Doyle, D. A.; Elkins, J. M. (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. Bibcode:2006PNAS..10317237Y. doi: 10.1073/pnas.0605779103 . PMC   1859916 . PMID   17085597.
  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 (November 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. doi:10.1128/CDLI.6.6.983-985.1999. PMC   95810 . PMID   10548598.
  3. ↑ Bridges D, Moorhead GB (August 2005). "14-3-3 proteins: a number of functions for a numbered protein". Science's STKE. 2005 (296): re10. doi:10.1126/stke.2962005re10. PMID   16091624. S2CID   5795342.
  4. ↑ "ELM search: "14-3-3"". Eukaryotic Linear Motif resource. Retrieved 16 May 2019.
  5. ↑ Madeira F, Tinti M, Murugesan G, Berrett E, Stafford M, Toth R, Cole C, MacKintosh C, Barton GJ (July 2015). "14-3-3-Pred: improved methods to predict 14-3-3-binding phosphopeptides". Bioinformatics. 31 (14): 2276–83. doi:10.1093/bioinformatics/btv133. PMC   4495292 . PMID   25735772.
  6. ↑ Aitken, A (2006). "14-3-3 proteins: a historic overview". Semin Cancer Biol. 50 (6): 993–1010. doi:10.1023/A:1021261931561. PMID   16678438. S2CID   41949194.
  7. ↑ Xu Z, Zan H, Pone EJ, Mai T, Casali P (June 2012). "Immunoglobulin class-switch DNA recombination: induction, targeting and beyond". Nat Rev Immunol. 12 (7): 517–31. doi:10.1038/nri3216. PMC   3545482 . PMID   22728528.
  8. ↑ Cann KL, Hicks GG (December 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.
  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. ↑ Abdelhafiz D, Kilborn S, Bukhari M (June 2021). "The role of 14-3-3 η as a biomarker in rheumatoid arthritis". Rheumatology and Immunology Research. 2 (2): 87–90. doi: 10.2478/rir-2021-0012 . PMC   9524784 . PMID   36465971. S2CID   238231522.
  11. ↑ Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, Ballif BA (October 2012). "RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation". The Biochemical Journal. 447 (1): 159–66. doi:10.1042/BJ20120938. PMC   4198020 . PMID   22827337.
  12. ↑ Jahn TP, Schulz A, Taipalensuu J, Palmgren MG (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): 6353–8. doi: 10.1074/jbc.M109637200 . PMID   11744700.

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