Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr;42(4):226-238.
doi: 10.1016/j.tips.2021.01.001. Epub 2021 Jan 28.

14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases

F Sanders Pair  1 , Talene A Yacoubian  2
Affiliations
Review

14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases

F Sanders Pair et al. Trends Pharmacol Sci. 2021 Apr.

Abstract

14-3-3 proteins are a family of proteins expressed throughout the body and implicated in many diseases, from cancer to neurodegenerative disorders. While these proteins do not have direct enzymatic activity, they form a hub for many signaling pathways via protein-protein interactions (PPIs). 14-3-3 interactions have proven difficult to target with traditional pharmacological methods due to the unique nature of their binding. However, recent advances in compound development utilizing a range of tools, from thermodynamic binding site analysis to computational molecular modeling techniques, have opened the door to targeting these interactions. Compounds are already being developed targeting 14-3-3 interactions with potential therapeutic implication for neurodegenerative disorders, but challenges still remain in optimizing specificity and target engagement to avoid unintended negative consequences arising from targeting 14-3-3 signaling networks.

Keywords: 14-3-3; Alzheimer’s disease; Parkinson’s disease; protein–protein interactions.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. 14-3-3ζ may promote tau hyper-phosphorylation and aggregation seen in Alzheimer’s Disease.
Within the axons of cortical neurons, normal tau phosphorylation and activity leads to microtubule stabilization. However, 14-3-3ζ can bind tau and makes it a better substrate for various kinases. Excessive tau phosphorylation can then promote tau aggregation and consequent destabilization of microtubules.
Figure 2.
Figure 2.. A theoretical framework for stabilizing the interaction between 14-3-3 and the imaginary Protein Z.
14-3-3-Pred can be used to find predicted binding sites. Once predicted sites are found, thermodynamic techniques such as fluorescence polarization and isothermal titration calorimetry can be used to determine which sites are critical to the 14-3-3/Protein Z interaction. Finally, cysteine trapping can be used to screen for compounds that stabilize the interaction between Protein Z and 14-3-3.
See this image and copyright information in PMC

References

    1. Martin H, et al. (1994) Subcellular localisation of 14-3-3 isoforms in rat brain using specific antibodies. J Neurochem 63, 2259–2265 - PubMed
    1. Baxter HC, et al. (2002) Specific 14-3-3 isoform detection and immunolocalization in prion diseases. Biochem Soc Trans 30, 387–391 - PubMed
    1. Moore BW (1967) Specific acidic proteins of the nervous system. Physiological and Biochemical Aspects of Nervous Integration, 343–359
    1. Moore BW, et al. (1968) ASSAY AND REGIONAL DISTRIBUTION OF A SOLUBLE PROTEIN CHARACTERISTIC OF THE NERVOUS SYSTEM*. Journal of Neurochemistry 15, 265–272 - PubMed
    1. Zhu H, et al. (2016) Origin of a folded repeat protein from an intrinsically disordered ancestor. Elife 5 - PMC - PubMed

Publication types

Substances