Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Obsil, T. et al.

Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding.

The 14-3-3 proteins, a family of dimeric regulatory proteins, are involved in many biologically important processes. The common feature of 14-3-3 proteins is their ability to bind to other proteins in a phosphorylation-dependent manner. Through these binding interactions, 14-3-3 proteins work as molecular scaffolds, modulating the biological functions of their partners. 14-3-3 proteins recognize short motifs containing a phosphorylated serine or threonine residue. In this study, we have quantitatively characterized the in vitro interactions among 14-3-3, the Forkhead transcription factor FOXO4, and its target DNA, the insulin response element. Phosphorylation of FOXO4 (residues 11-213) by protein kinase B at Thr-28 and Ser-193 creates two 14-3-3 binding motifs. Analytical gel filtration and sedimentation equilibrium experiments indicate that doubly phosphorylated FOXO4 and 14-3-3zeta form a complex with 1:2 molar stoichiometry and a K(D) of less than 30 nM. In contrast, singly phosphorylated FOXO4 mutants bind 14-3-3zeta with significantly lower affinity while retaining the ability to bind DNA. An active role for 14-3-3 in the disassembly of the FOXO4/DNA complex is demonstrated by the fact that, in the presence of 14-3-3, two phosphorylated 14-3-3 binding motifs are needed for the complete inhibition of FOXO4 binding to its target DNA.[1]

References

Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Obsil, T., Ghirlando, R., Anderson, D.E., Hickman, A.B., Dyda, F. Biochemistry (2003) [Pubmed]

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