Alternative titles; symbols
HGNC Approved Gene Symbol: YWHAH
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:31,944,535-31,957,603 (from NCBI)
Protein 14-3-3 is a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases (191290, 191060) and an endogenous inhibitor of protein kinase C (176960). The 14-3-3 protein exists in several distinct forms: e.g., beta (YWHAB; 601289), gamma (YWHAG; 605356), epsilon (YWHAE; 605066), zeta (YWHAZ; 601288), theta (YWHAQ; 609009), sigma (SFN; 601290), and eta (YWHAH).
Ichimura-Ohshima et al. (1992) reported a cDNA clone of mRNA encoding human 14-3-3 protein. The 1,730-nucleotide sequence of the cDNA contained a 191-bp 5-prime noncoding region, the complete 738-bp coding region, and an 801-bp 3-prime noncoding region with 3 canonical polyadenylation signals. The eta chain encoded by the cDNA is a 246-amino acid polypeptide with a predicted molecular weight of 28,196. The predicted amino acid sequence of the human 14-3-3 protein eta was highly homologous to that of previously reported bovine and rat proteins with only 2 amino acid differences. Northern blot analysis demonstrated widespread expression of the eta chain in cultured cell lines derived from various human tumors.
Muratake et al. (1996) determined that the human YWHAH gene has 2 exons separated by an intron of approximately 8 kb. Using S1 nuclease mapping, primer extension, and RACE PCR, Muratake et al. (1996) identified the transcription initiation site. They also identified several regulatory element sequences, including CRE, in the 5-prime noncoding region. Muratake et al. (1996) noted that the presence of a CRE binding element may indicate that this gene is involved in brain responses to narcotics. The authors also found changes in a 7-bp repeat sequence (GCCTGCA) located in the noncoding region of exon 1 and they speculated that these changes, or other changes in the sequence of this gene, may be associated with neuropsychiatric disorders.
Cryoelectron Microscopy
Park et al. (2019) used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF (164757) in complexes with MEK1 (176872) and a 14-3-3 dimer of eta (YWHAH) and zeta (YWHAZ; 601288). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer.
Ichimura-Ohshima et al. (1992) used spot blot hybridization analysis with flow sorted chromosomes to show that the eta chain is located on chromosome 22. Tommerup and Leffers (1996) mapped the YWHAH gene to 22q12 by fluorescence in situ hybridization (FISH). Muratake et al. (1996) used FISH to refine the mapping of the YWHAH gene to 22q12.1-q13.1.
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 (601288) 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.
Simsek-Duran et al. (2004) found that a 14-3-3 protein from rodent brain lysate bound phosphorylated residue ser413 of the Rim1 (606629) protein, whereas it did not bind to nonphosphorylatable Rim1 mutants. Presynaptic transfection with a dominant-negative 14-3-3-eta mutant protein, which showed reduced binding to Rim1, inhibited mouse cerebellar long-term potentiation (LTP). The authors concluded that 14-3-3 is a necessary downstream component of the ser413-Rim1 pathway involved in presynaptic LTP; however, they noted that the brain 14-3-3 isoform could not be identified definitively as eta.
Ichimura-Ohshima, Y., Morii, K., Ichimura, T., Araki, K., Takahashi, Y., Isobe, T., Minoshima, S., Fukuyama, R., Shimizu, N., Kuwano, R. cDNA cloning and chromosome assignment of the gene for human brain 14-3-3 protein eta chain. J. Neurosci. Res. 31: 600-605, 1992. [PubMed: 1578511] [Full Text: https://doi.org/10.1002/jnr.490310403]
Muratake, T., Hayashi, S., Ichikawa, T., Kumanishi, T., Ichimura, Y., Kuwano, R., Isobe, T., Wang, Y., Minoshima, S., Shimizu, N., Takahashi, Y. Structural organization and chromosomal assignment of the human 14-3-3-eta chain gene (YWHAH). Genomics 36: 63-69, 1996. [PubMed: 8812417] [Full Text: https://doi.org/10.1006/geno.1996.0426]
Park, E., Rawson, S., Li, K., Kim, B.-W., Ficarro, S. B., Gonzalez-Del Pino, G., Sharif, H., Marto, J. A., Jeon, H., Eck, M. J. Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature 575: 545-550, 2019. [PubMed: 31581174] [Full Text: https://doi.org/10.1038/s41586-019-1660-y]
Simsek-Duran, F., Linden, D. J., Lonart, G. Adapter protein 14-3-3 is required for a presynaptic form of LTP in the cerebellum. Nature Neurosci. 7: 1296-1298, 2004. [PubMed: 15543142] [Full Text: https://doi.org/10.1038/nn1348]
Tommerup, N., Leffers, H. Assignment of the human genes encoding 14-3-3 eta (YWHAH) to 22q12, 14-3-3 zeta (YWHAZ) to 2p25.1-p25.2, and 14-3-3 beta (YWHAB) to 20q13.1 by in situ hybridization. Genomics 33: 149-150, 1996. [PubMed: 8617504] [Full Text: https://doi.org/10.1006/geno.1996.0176]
Yaffe, M. B., Rittinger, K., Volinia, S., Caron, P. R., Aitken, A., Leffers, H., Gamblin, S. J., Smerdon, S. J., Cantley, L. C. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91: 961-971, 1997. [PubMed: 9428519] [Full Text: https://doi.org/10.1016/s0092-8674(00)80487-0]