Structural basis for protein–protein interactions in the 14-3-3 protein family

Structural Genomics Consortium, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2006; 103(46):17237-42. DOI: 10.1073/pnas.0605779103
Source: PubMed

ABSTRACT The seven members of the human 14-3-3 protein family regulate a diverse range of cell signaling pathways by formation of protein-protein complexes with signaling proteins that contain phosphorylated Ser/Thr residues within specific sequence motifs. Previously, crystal structures of three 14-3-3 isoforms (zeta, sigma, and tau) have been reported, with structural data for two isoforms deposited in the Protein Data Bank (zeta and sigma). In this study, we provide structural detail for five 14-3-3 isoforms bound to ligands, providing structural coverage for all isoforms of a human protein family. A comparative structural analysis of the seven 14-3-3 proteins revealed specificity determinants for binding of phosphopeptides in a specific orientation, target domain interaction surfaces and flexible adaptation of 14-3-3 proteins through domain movements. Specifically, the structures of the beta isoform in its apo and peptide bound forms showed that its binding site can exhibit structural flexibility to facilitate binding of its protein and peptide partners. In addition, the complex of 14-3-3 beta with the exoenzyme S peptide displayed a secondary structural element in the 14-3-3 peptide binding groove. These results show that the 14-3-3 proteins are adaptable structures in which internal flexibility is likely to facilitate recognition and binding of their interaction partners.

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Available from: Jörg Günter Grossmann, Aug 23, 2015
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    • "(B) illustrates the formation of possible dimers within the mammalian 14-3-3 protein family. The reported interactions are shown between different monomers by formation of heterodimers (14-3-3e/YWHAE with 14-3-3b/YWHAB, 14-3-3g/ YWHAG, 14-3-3h/YWHAH, 14-3-3z/YWHAZ, and 14-3-3t/YWHAQ) and by formation of homodimers [Yang et al., 2006]. 14-3-3s/YWHAS is found to preferentially form homodimers, whereas YWHAE is found as heterodimers in cells. "
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    • "Several studies have shown tissue and/or cell cycle phase specific expression of 14-3-3 isoforms (Moreira et al., 2008). Structural data show little divergence in the phosphopeptide-binding pockets of the 14- 3-3 paralogs (Yang et al., 2006), and because most 14-3-3 binding motifs conform to a few consensus sequences, it seems that isoform specificity does not reside in the binding site of the 14-3-3 partners (Uhart et al., 2011). Indeed, it most likely depends on additional contacts with the partner, probably involving residues such as anchors (Rajamani et al., 2004), outside the 14-3-3 binding motifs on the 14-3-3 partners (Uhart et al., 2011; Bier et al., 2013). "
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    Frontiers in Genetics 02/2014; 5:10. DOI:10.3389/fgene.2014.00010
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