7V9B

Crystal Structure of 14-3-3 epsilon with FOXO3a peptide

Summary for 7V9B

• Entry DOI: 10.2210/pdb7v9b/pdb
• Descriptor: YWHAE/FAM22B fusion protein, ARG-ARG-ARG-ALA-VAL-SEP-MET-ASP-ASN-SER-ASN, GLYCEROL, ... (7 entities in total)
• Functional Keywords: foxo3a, 14-3-3, 14-3-3 epsilon, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30455.53

Authors

Mathivanan, S.,Kamariah, N. (deposition date: 2021-08-24, release date: 2022-08-31, Last modification date: 2023-11-29)

Primary citation

Mathivanan, S.,Chunchagatta Lakshman, P.K.,Singh, M.,Giridharan, S.,Sathish, K.,Hurakadli, M.A.,Bharatham, K.,Kamariah, N.
Structure of a 14-3-3 epsilon :FOXO3a pS253 Phosphopeptide Complex Reveals 14-3-3 Isoform-Specific Binding of Forkhead Box Class O Transcription Factor (FOXO) Phosphoproteins.
Acs Omega, 7:24344-24352, 2022

PubMed Abstract: The transcriptional activity of Forkhead Box O3 (FOXO3a) is inactivated by AKT-mediated phosphorylation on Serine 253 (S253), which enables FOXO3a binding to 14-3-3. Phosphorylated FOXO3a binding to 14-3-3 facilitates the nuclear exclusion of FOXO3a, causing cancer cell proliferation. The FOXO3a/14-3-3 interaction has, therefore, emerged as an important therapeutic target. Here, we report a comprehensive analysis using fluorescence polarization, isothermal titration calorimetry, small-angle X-ray scattering, X-ray crystallography, and molecular dynamics simulations to gain molecular-level insights into the interaction of FOXO3a phosphopeptide with 14-3-3ε. A high-resolution structure of the fluorophore-labeled FOXO3a:14-3-3ε complex revealed a distinct mode of interaction compared to other 14-3-3 phosphopeptide complexes. FOXO3a phosphopeptide showed significant structural difference in the positions of the -3 and -4 Arg residues relative to pSer, compared to that of a similar phosphopeptide, FOXO1 bound to 14-3-3σ. Moreover, molecular dynamics studies show that the significant structural changes and molecular interactions noticed in the crystal structure of FOXO3a:14-3-3ε are preserved over the course of the simulation. Thus, this study reveals structural differences between the binding to 14-3-3 isoforms of FOXO1 versus FOXO3a, providing a framework for the rational design of isoform-specific FOXO/14-3-3 protein-protein interaction inhibitors for therapy.

PubMed: 35874228
DOI: 10.1021/acsomega.2c01700

Experimental method

X-RAY DIFFRACTION (1.85 Å)