14-3-3 protein zeta/delta (YWHAZ)

The protein contains 245 amino acids for an estimated molecular weight of 27745 Da.

 

Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (PubMed:16959763). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (By similarity). (updated: July 3, 2019)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

Interpro domains
Total structural coverage: 100%
Model score: 100
No model available.

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VariantDescription
Found in a patient with a neurodevelopmental disorder; unknown pathological significance
Found in a patient with a neurodevelopmental disorder; unknown pathological significance
Found in a patient with a neurodevelopmental disorder; unknown pathological significance; gain-of-function mutation in signal transduction; changed re

The reference OMIM entry for this protein is 601288

Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta isoform; ywhaz
Brain protein 14-3-3, zeta isoform
14-3-3-zeta

CLONING

The highly conserved 14-3-3 proteins are found in both plants and mammals. Some have been shown to be involved in the activation of c-Raf (164760) by their participation in the protein kinase C signaling pathway (see 176960). Leffers et al. (1993) reported the cloning of 14-3-3-zeta. See YWHAH (113508) and YWHAB (601289). Watanabe et al. (1994) isolated the rat zeta isoform of 14-3-3 from rat brain. The deduced 245-amino acid protein shares high sequence homology with other 14-3-3 subtypes. The zeta mRNA was widely expressed in various gray matter brain regions, including the neocortex, hippocampus, caudate-putamen, thalamus, cerebellar cortex, and several brain stem nuclei. A human protein with phospholipase A2 activity was shown to be the zeta subtype of the 14-3-3 protein (Zupan et al., 1992).

BIOCHEMICAL FEATURES

The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, Yaffe et al. (1997) identified 2 different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of YWHAZ complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6-angstrom resolution. The authors showed that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD (603167), and Cbl.

GENE FUNCTION

The binding of insulin (176730) to its receptor induces the phosphorylation of the cytosolic substrates IRS1 (147545) and IRS2 (600797), which associate with several Src homology-2 (SH2) domain-containing proteins. To identify unique IRS1-binding proteins, Ogihara et al. (1997) screened a human heart cDNA expression library with recombinant IRS1. They obtained 2 isoforms of the 14-3-3 protein family, 14-3-3-zeta and -epsilon (YWHAE; 605066). 14-3-3 protein has been shown to associate with IRS1 in L6 myotubes, HepG2 hepatoma cells, Chinese hamster ovary cells, and bovine brain tissue. The amount of 14-3-3 protein associated with IRS1 was not affected by insulin stimulation but was increased significantly by treatment with okadaic acid, a potent serine/threonine phosphatase inhibitor. The authors identified a putative 14-3-3 protein-binding site within the phosphotyrosine-binding (PTB) domain of IRS1. Ogihara et al. (1997) suggested that the association with 14-3-3 protein may play a role in the regulation of insulin sensitivity by interrupting the association between the insulin receptor and IRS1. Using 2-hybrid experiments, Han et al. (1997) demonstrated interaction between murine Ywhaz and the RAS-binding domain of RIN1 (605965). Using in vitro pull-down assays, Powell et al. (2002) showed that recombinant 14-3-3-zeta interacted directly with both recombinant and endogenous protein kinase B (PKB, or AKT1; 164730) within embryonic kidney cell lysates. They found that recombinant PKB phosphorylated 14-3-3-zeta in an in vitro kinase assay, and transfection of active PKB into embryonic kidney cells resulted in phosphorylation of 14-3-3-zeta. By mutation analysis, Powell et al. (2002) determined that the phosphate acceptor was serine-58. They also showed that phosphorylation did not result in 14-3-3-zeta dimerization. Serotonin N-acetyltransferase (AANAT; 600950) controls daily changes ... More on the omim web site

Subscribe to this protein entry history

July 4, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 15, 2016: Protein entry updated
Automatic update: OMIM entry 601288 was added.

Jan. 27, 2016: Protein entry updated
Automatic update: model status changed

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed