8.A.98.  The 14-3-3 protein (14-3-3) Family

The 14-3-3 proteins comprise a family of highly conserved, multifunctional proteins that are expressed in many tissues including the brain, especially during development. The seven human 14-3-3 isoforms make up approximately 1% of total soluble brain protein. These proteins play a role in cortical development, and regulate a number of neurodevelopmental processes. 14-3-3 isoforms play different roles in the development of the cortex and in human neurodevelopmental disorders (Cornell and Toyo-Oka 2017). The urea transporter, UT-A1 (TC# 1.A.28.1.3) is regulated by 14-3-3, which blocks its removal from the membrane (Klein and Sands 2016). TASK-1 (KCNK3; TC# 1.A.1.9.2) and TASK-3 (KCNK9; TC#1.A.1.19.11) K+ channels interact with 14-3-3 proteins, interactions that may influcence  targetting of these channels to the plasma membrane (Kilisch et al. 2015).The Nedd4-2 ubiquitin ligase binds 14-3-3, blocking its interaction with Orai1 and thus its degradation (Lang et al. 2012). In fact, 14-3-3 proteins regulate several aspects of intracellular transport (Smith et al. 2011). Most interacting proteins, such as the two pore K+ channels, KCNK3 and KCNK9 (see above), have 14-3-3 motifs for binding to this protein (Mrowiec and Schwappach 2006). These proteins also regulate sucrose/glucose/fructose:H+ symporters of the SLC49 family (TC#2.A.2.4) (Vitavska et al. 2018).


 

References:

Asih, P.R., A. Poljak, M. Kassiou, Y.D. Ke, and L.M. Ittner. (2022). Differential mitochondrial protein interaction profile between human translocator protein and its A147T polymorphism variant. PLoS One 17: e0254296.

Cornell, B. and K. Toyo-Oka. (2017). 14-3-3 Proteins in Brain Development: Neurogenesis, Neuron.al Migration and Neuromorphogenesis. Front Mol Neurosci 10: 318.

Gu, Y.M., Y.H. Jin, J.K. Choi, K.H. Baek, C.Y. Yeo, and K.Y. Lee. (2006). Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon. FEBS Lett. 580: 305-310.

Jin, Y., M.S. Dai, S.Z. Lu, Y. Xu, Z. Luo, Y. Zhao, and H. Lu. (2006). 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO. J. 25: 1207-1218.

Kilisch, M., O. Lytovchenko, B. Schwappach, V. Renigunta, and J. Daut. (2015). The role of protein-protein interactions in the intracellular traffic of the potassium channels TASK-1 and TASK-3. Pflugers Arch 467: 1105-1120.

Klein, J.D. and J.M. Sands. (2016). Urea transport and clinical potential of urearetics. Curr Opin Nephrol Hypertens 25: 444-451.

Lang, F., A. Eylenstein, and E. Shumilina. (2012). Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK. Cell Calcium 52: 347-354.

Mrowiec, T. and B. Schwappach. (2006). 14-3-3 proteins in membrane protein transport. Biol Chem 387: 1227-1236.

Smith, A.J., J. Daut, and B. Schwappach. (2011). Membrane proteins as 14-3-3 clients in functional regulation and intracellular transport. Physiology (Bethesda) 26: 181-191.

Suhda, S., Y. Yamamoto, S. Wisesa, R. Sada, and T. Sakisaka. (2023). The 14-3-3γ isoform binds to and regulates the localization of endoplasmic reticulum (ER) membrane protein TMCC3 for the reticular network of the ER. J. Biol. Chem. 299: 102813.

Tsuruta, F., J. Sunayama, Y. Mori, S. Hattori, S. Shimizu, Y. Tsujimoto, K. Yoshioka, N. Masuyama, and Y. Gotoh. (2004). JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO. J. 23: 1889-1899.

Vitavska, O., R. Bartölke, K. Tabke, J.J. Heinisch, and H. Wieczorek. (2018). Interaction of mammalian and plant H/sucrose transporters with 14-3-3 proteins. Biochem. J. 475: 3239-3254.

Wang, X., N. Grammatikakis, A. Siganou, and S.K. Calderwood. (2003). Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3 epsilon binding, and cytoplasmic sequestration of heat shock factor 1. Mol. Cell Biol. 23: 6013-6026.

Zhou, Y., S. Reddy, H. Murrey, H. Fei, and I.B. Levitan. (2003). Monomeric 14-3-3 protein is sufficient to modulate the activity of the Drosophila slowpoke calcium-dependent potassium channel. J. Biol. Chem. 278: 10073-10080.

Examples:

TC#NameOrganismal TypeExample
8.A.98.1.1

The dimeric fly 14-3-3zeta protein of 248 aas modulates as a negative regulator to control the activity of the Slowpoke calcium-dependent potassium channel (dSlo) by interacting with the dSlo binding protein, Slob (Zhou et al. 2003).

14.3.3zeta of Drosophila melanogaster (Fruit fly)

 
8.A.98.1.10

14-3-3 protein epsilon , 14-3-3ε, of 255 aas and 0 TMSs.  It positively regulates phosphorylated protein HSF1 (Q00613; 529 aas, 0 TMSs) nuclear export to the cytoplasm (Wang et al. 2003).

 

14-3-3ε adaptor protein of Homo sapiens

 
8.A.98.1.11

14-3-3 protein gamma, 14-3-3γ or YWHAG, of 247 aas and 0 TMSs. It is an adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. It 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 (Jin et al. 2006).  The 14-3-3gamma isoform binds to and regulates the localization of endoplasmic reticulum (ER) membrane protein TMCC3 for the reticular network of the ER (Suhda et al. 2023).

14-3-3γ of Homo sapiens

 
8.A.98.1.2

14-3-3zeta/delta protein of 245 aas, an adapter protein implicated in the regulation of a large number of signaling systems and transport proteins. It binds to its partners, often by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the target partner protein (Tsuruta et al. 2004; Gu et al. 2006).

14-3-3 of Homo sapiens

 
8.A.98.1.3

14-3-3 protein of 262 aas.

14-3-3 of Plasmodium falciparum

 
8.A.98.1.4

14-3-3ε protein of 169 aas

14-3-3ε of Tetrahymena thermophila

 
8.A.98.1.5

Uncharacterized protein of 212 aas.

UP of Ascaris suum (Pig roundworm) (Ascaris lumbricoides)

 
8.A.98.1.6

14-3-3 protein of 363 aas.

14-3-3 protein of Glarea lozoyensis

 
8.A.98.1.7

14-3-3 homologue of 233 aas.

14-3-3 of Reticulomyxa filosa

 
8.A.98.1.8

14-3-3 protein, GF14λ, ATF1, RCI2, of 248 aas

14-3-3 protein of Arabidopsis thaliana

 
8.A.98.1.9

14-3-3 theta (YWHAQ) of 245 aas and 0 TMSs. It is an adapter protein implicated in the regulation of several general and specialized signaling pathways. It 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 (Asih et al. 2022).

YWHAQ of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.98.2.1

Uncharacterized protein of 294 aas and 1 N-terminal TMS.

UP of Streptococcus iniae