Article

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

Department of Chemistry, University of Cambridge, Cambridge, England, United Kingdom
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 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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    • "We generated a structural model of yeast dimeric Bmh1p to locate the amino acid changes and truncation on the 3D protein structure. We used its homology with the human protein 2BR9, whose structure has been resolved by crystallography (Yang et al. 2006, see Supporting Information and Material and methods). Arbitrary and specific docking predictions were then carried out (see Supporting Information and Material and methods). "
    Dataset: spor2013

    Full-text · Dataset · Sep 2015
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    • "We generated a structural model of yeast dimeric Bmh1p to locate the amino acid changes and truncation on the 3D protein structure. We used its homology with the human protein 2BR9, whose structure has been resolved by crystallography (Yang et al. 2006, see Supporting Information and Material and methods). Arbitrary and specific docking predictions were then carried out (see Supporting Information and Material and methods). "
    Dataset: spor2013

    Full-text · Dataset · Sep 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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    ABSTRACT: Monoamines critically modulate neurophysiological functions affected in several neuropsychiatric disorders. We therefore examined genes encoding key enzymes of catecholamine and serotonin biosynthesis (tyrosine and tryptophan hydroxylases-TH and TPH1/2) as well as their regulatory 14-3-3 proteins (encoded by YWHA-genes). Previous studies have focused mainly on the individual genes, but no analysis spanning this regulatory network has been reported. We explored interactions between these genes in Norwegian patients with adult attention deficit hyperactivity disorder (aADHD), followed by gene-complex association tests in four major neuropsychiatric conditions; childhood ADHD (cADHD), bipolar disorder, schizophrenia, and major depressive disorder. For interaction analyses, we evaluated 55 SNPs across these genes in a sample of 583 aADHD patients and 637 controls. For the gene-complex tests, we utilized the data from large-scale studies of The Psychiatric Genomics Consortium (PGC). The four major neuropsychiatric disorders were examined for association with each of the genes individually as well as in three complexes as follows: (1) TPH1 and YWHA-genes; (2) TH, TPH2 and YWHA-genes; and (3) all genes together. The results show suggestive epistasis between YWHAE and two other 14-3-3-genes - YWHAZ, YWHAQ - in aADHD (nominal P-value of 0.0005 and 0.0008, respectively). In PGC data, association between YWHAE and schizophrenia was noted (P = 1.00E-05), whereas the combination of TPH1 and YWHA-genes revealed signs of association in cADHD, schizophrenia, and bipolar disorder. In conclusion, polymorphisms in the YWHA-genes and their targets may exert a cumulative effect in ADHD and related neuropsychiatric conditions, warranting the need for further investigation of these gene-complexes. © 2015 Wiley Periodicals, Inc. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
    Full-text · Article · Jul 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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