Contemporary Biophysical Approaches for Studying 14-3-3 Protein-protein Interactions

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2022 Nov 25

PMID 36425654

Authors

Bethany Thurairajah

Andrew J Hudson

Richard G Doveston

Affiliations

Soon will be listed here.

Abstract

14-3-3 proteins are a family of regulatory hubs that function through a vast network of protein-protein interactions. Their dysfunction or dysregulation is implicated in a wide range of diseases, and thus they are attractive drug targets, especially for molecular glues that promote protein-protein interactions for therapeutic intervention. However, an incomplete understanding of the molecular mechanisms that underpin 14-3-3 function hampers progress in drug design and development. Biophysical methodologies are an essential element of the 14-3-3 analytical toolbox, but in many cases have not been fully exploited. Here, we present a contemporary review of the predominant biophysical techniques used to study 14-3-3 protein-protein interactions, with a focus on examples that address key questions and challenges in the 14-3-3 field.

References

Cossar P, Wolter M, van Dijck L, Valenti D, Levy L, Ottmann C . Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions. J Am Chem Soc. 2021; 143(22):8454-8464. PMC: 8193639. DOI: 10.1021/jacs.1c03035. View

Boozer C, Kim G, Cong S, Guan H, Londergan T . Looking towards label-free biomolecular interaction analysis in a high-throughput format: a review of new surface plasmon resonance technologies. Curr Opin Biotechnol. 2006; 17(4):400-5. DOI: 10.1016/j.copbio.2006.06.012. View

Kast D, Dominguez R . Mechanism of IRSp53 inhibition by 14-3-3. Nat Commun. 2019; 10(1):483. PMC: 6351565. DOI: 10.1038/s41467-019-08317-8. View

Sijbesma E, Hallenbeck K, Andrei S, Rust R, Adriaans J, Brunsveld L . Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers. ACS Med Chem Lett. 2021; 12(6):976-982. PMC: 8201753. DOI: 10.1021/acsmedchemlett.1c00088. View

Gogl G, Tugaeva K, Eberling P, Kostmann C, Trave G, Sluchanko N . Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms. Nat Commun. 2021; 12(1):1677. PMC: 7961048. DOI: 10.1038/s41467-021-21908-8. View

de Vink P, Andrei S, Higuchi Y, Ottmann C, Milroy L, Brunsveld L . Cooperativity basis for small-molecule stabilization of protein-protein interactions. Chem Sci. 2019; 10(10):2869-2874. PMC: 6429609. DOI: 10.1039/c8sc05242e. View

Bellamy-Carter J, Mohata M, Falcicchio M, Basran J, Higuchi Y, Doveston R . Discovering protein-protein interaction stabilisers by native mass spectrometry. Chem Sci. 2021; 12(32):10724-10731. PMC: 8372317. DOI: 10.1039/d1sc01450a. View

Fuglsang A, VISCONTI S, Drumm K, Jahn T, Stensballe A, Mattei B . Binding of 14-3-3 protein to the plasma membrane H(+)-ATPase AHA2 involves the three C-terminal residues Tyr(946)-Thr-Val and requires phosphorylation of Thr(947). J Biol Chem. 1999; 274(51):36774-80. DOI: 10.1074/jbc.274.51.36774. View

Leysen S, Burnley R, Rodriguez E, Milroy L, Soini L, Adamski C . A Structural Study of the Cytoplasmic Chaperone Effect of 14-3-3 Proteins on Ataxin-1. J Mol Biol. 2021; 433(19):167174. PMC: 8505757. DOI: 10.1016/j.jmb.2021.167174. View

10.

Gordon G, Berry G, Liang X, Levine B, Herman B . Quantitative fluorescence resonance energy transfer measurements using fluorescence microscopy. Biophys J. 1998; 74(5):2702-13. PMC: 1299610. DOI: 10.1016/S0006-3495(98)77976-7. View

11.

Pennington K, Chan T, Torres M, Andersen J . The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein-protein interactions. Oncogene. 2018; 37(42):5587-5604. PMC: 6193947. DOI: 10.1038/s41388-018-0348-3. View

12.

Trosanova Z, Lousa P, Kozelekova A, Brom T, Gasparik N, Tungli J . Quantitation of Human 14-3-3ζ Dimerization and the Effect of Phosphorylation on Dimer-monomer Equilibria. J Mol Biol. 2022; 434(7):167479. DOI: 10.1016/j.jmb.2022.167479. View

13.

Soini L, Redhead M, Westwood M, Leysen S, Davis J, Ottmann C . Identification of molecular glues of the SLP76/14-3-3 protein-protein interaction. RSC Med Chem. 2021; 12(9):1555-1564. PMC: 8459327. DOI: 10.1039/d1md00172h. View

14.

Du X, Li Y, Xia Y, Ai S, Liang J, Sang P . Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods. Int J Mol Sci. 2016; 17(2). PMC: 4783878. DOI: 10.3390/ijms17020144. View

15.

Wolter M, de Vink P, Neves J, Srdanovic S, Higuchi Y, Kato N . Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products. J Am Chem Soc. 2020; 142(27):11772-11783. PMC: 8022324. DOI: 10.1021/jacs.0c02151. View

16.

Hartman A, Elgaher W, Hertrich N, Andrei S, Ottmann C, Hirsch A . Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry. ACS Med Chem Lett. 2020; 11(5):1041-1046. PMC: 7236542. DOI: 10.1021/acsmedchemlett.9b00541. View

17.

Kozelekova A, Naplavova A, Brom T, Gasparik N, Simek J, Houser J . Phosphorylated and Phosphomimicking Variants May Differ-A Case Study of 14-3-3 Protein. Front Chem. 2022; 10:835733. PMC: 8935074. DOI: 10.3389/fchem.2022.835733. View

18.

Falcicchio M, Ward J, Macip S, Doveston R . Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer. Cell Death Discov. 2020; 6(1):126. PMC: 7669891. DOI: 10.1038/s41420-020-00362-3. View

19.

Wolter M, Valenti D, Cossar P, Hristeva S, Levy L, Genski T . An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB-Utilizing a Reversible Covalent Tethering Approach. J Med Chem. 2021; 64(12):8423-8436. PMC: 8237268. DOI: 10.1021/acs.jmedchem.1c00401. View

20.

Stevers L, Wolter M, Carlile G, Macdonald D, Richard L, Gielkens F . Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR. Nat Commun. 2022; 13(1):3586. PMC: 9226124. DOI: 10.1038/s41467-022-31206-6. View