Structural Characterization of Phosducin and Its Complex with the 14-3-3 Protein

Kacirova, Miroslava; Košek, Dalibor; Kádek, Alan; Man, Petr; Večeř, Jaroslav; Heřman, Petr; Obšilová, Veronika; Obšil, Tomáš

doi:10.1074/jbc.m115.636563

Cited by 22 publications

(17 citation statements)

References 62 publications

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“…Here, control of subcellular localization, enzymatic activity, and biological half-life can be envisioned as modes by which 14-3-3 PPI modulators could act, e.g., on transcription factors (YAP, c-Jun, MLF1, FOXOs), enzymes shuttling between cytoplasm and nucleus (Cdc25 phosphatases, HDACs), or kinases (B, C-Raf, LRRK2). In recent years, a growing number of crystal structures of 14-3-3 in complex with different binding partner motifs have been published, for example, the cystic fibrosis ion channel CFTR, 55 the small heat shock protein HSPB6, 56 phosducin, 57 and the Parkinson's disease-related kinase LRRK2. 58 As dimeric species that dock onto pairs of specific phosphorylated serine-or threonine-containing motifs, 14-3-3 proteins are endowed with special signaling, mechanical, and evolutionary properties.…”

Section: Intentionally Targetingmentioning

confidence: 99%

“…59,60 14-3-3 binding sites lie within motifs that are phosphorylated by basophilic protein kinases such as PKB/Akt, p90RSK, PKA, and AMPK. 57 This means that 14-3-3 affinity capture and quantitative mass spectrometry procedures can be used to identify targets of, for example, regulation by insulin, growth factors, energy stress, and adrenalin that activate these respective kinases. In this way, new 14-3-3-based mechanisms have been identified to explain how insulin and growth factors regulate synchronized shifts in glucose uptake, glycolysis, mTORC1 signaling, protein translation, and other regulatory events that promote cell growth and proliferation.…”

Section: Intentionally Targetingmentioning

confidence: 99%

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Modulators of Protein–Protein Interactions

et al. 2014

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Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

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Section: Intentionally Targetingmentioning

confidence: 99%

Section: Intentionally Targetingmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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“…Therefore, it is unlikely that phosphorylation alone interferes with GCAP2 binding to RetGC in vitro or in vivo . However, we have shown that phosphorylation at Ser201 triggers 14-3-3 binding to GCAP2 in vivo 41 , an step that could conceivably hinder GCAP2 binding to RetGC, in a similar way as 14-3-3 binding to phosphorylated phosducin masks its binding sites to Gβγ 62 , 63 .…”

Section: Discussionmentioning

confidence: 86%

Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina

López-Begines

Plana-Bonamaisó

Méndez

2018

Sci Rep

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Retinal guanylate cyclase (RetGC) and guanylate cyclase activating proteins (GCAPs) play an important role during the light response in photoreceptor cells. Mutations in these proteins are linked to distinct forms of blindness. RetGC and GCAPs exert their role at the ciliary outer segment where phototransduction takes place. We investigated the mechanisms governing GCAP1 and GCAP2 distribution to rod outer segments by expressing selected GCAP1 and GCAP2 mutants as transient transgenes in the rods of GCAP1/2 double knockout mice. We show that precluding GCAP1 direct binding to RetGC (K23D/GCAP1) prevented its distribution to rod outer segments, while preventing GCAP1 activation of RetGC post-binding (W94A/GCAP1) did not. We infer that GCAP1 translocation to the outer segment strongly depends on GCAP1 binding affinity for RetGC, which points to GCAP1 requirement to bind to RetGC to be transported. We gain further insight into the distinctive regulatory steps of GCAP2 distribution, by showing that a phosphomimic at position 201 is sufficient to retain GCAP2 at proximal compartments; and that the bovine equivalent to blindness-causative mutation G157R/GCAP2 results in enhanced phosphorylation in vitro and significant retention at the inner segment in vivo, as likely contributing factors to the pathophysiology.

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“…Although not directly compared, less 14-3-3 isoform selectivity would therefore be expected for serotonin N-acetyltransferase. The 14-3-3 target proteins RGS3 and phosducin show interactions outside the binding groove, in a less conserved area of 14-3-3 (Kacirova et al 2015 ; Rezabkova et al 2011 ). For neither RGS3 nor phosducin the binding affinities to the different 14-3-3 isoforms have been compared, although RGS3 is reported to interact with 14-3-3β and τ in addition to 14-3-3ζ (Benzing et al 2000 ; Niu et al 2002 ; Rezabkova et al 2011 ).…”

Section: Resultsmentioning

confidence: 99%

Regulation of tyrosine hydroxylase is preserved across different homo- and heterodimeric 14-3-3 proteins

et al. 2016

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Tyrosine hydroxylase (TH) is regulated by members of the 14-3-3 protein family. However, knowledge about the variation between 14-3-3 proteins in their regulation of TH is still limited. We examined the binding, effects on activation and dephosphorylation kinetics of tyrosine hydroxylase (TH) by abundant midbrain 14-3-3 proteins (β, η, ζ, γ and ε) of different dimer composition. All 14-3-3 homodimers and their respective 14-3-3ε-heterodimers bound with similar high affinity (Kd values of 1.4–3.8 nM) to serine19 phosphorylated human TH (TH-pS19). We similarly observed a consistent activation of bovine (3.3- to 4.4-fold) and human TH-pS19 (1.3–1.6 fold) across all the different 14-3-3 dimer species, with homodimeric 14-3-3γ being the strongest activator. Both hetero- and homodimers of 14-3-3 strongly inhibited dephosphorylation of TH-pS19, and we speculate if this is an important homeostatic mechanism of 14-3-3 target-protein regulation in vivo. We conclude that TH is a robust interaction partner of different 14-3-3 dimer types with moderate variability between the 14-3-3 dimers on their regulation of TH.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-015-2157-0) contains supplementary material, which is available to authorized users.

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Structural Characterization of Phosducin and Its Complex with the 14-3-3 Protein

Cited by 22 publications

References 62 publications

Modulators of Protein–Protein Interactions

Modulators of Protein–Protein Interactions

Molecular determinants of Guanylate Cyclase Activating Protein subcellular distribution in photoreceptor cells of the retina

Regulation of tyrosine hydroxylase is preserved across different homo- and heterodimeric 14-3-3 proteins

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