The role of the 14-3-3 protein family in health, disease, and drug development

Aghazadeh, Yasaman; Papadopoulos, Vassilios

doi:10.1016/j.drudis.2015.09.012

Cited by 223 publications

(203 citation statements)

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“…They are involved in a wide variety of biological processes, including intracellular signaling, cell-cycle control, apoptosis, and protein trafficking. 40 Knockdown of 14-3-3g in zebrafish resulted in delayed brain development, reduced brain size, and increased diameter of the heart tube. 41 Curiously, in mice, a decrease or increase in 14-3-3g leads to delayed neuronal migration of pyramidal neurons in the cerebral cortex.…”

mentioning

confidence: 99%

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Guella

McKenzie

Evans

et al. 2017

The American Journal of Human Genetics

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Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3g) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n ¼ 1) and YWHAG (n ¼ 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.

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confidence: 99%

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Guella

McKenzie

Evans

et al. 2017

The American Journal of Human Genetics

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“…14-3-3 protein epsilon This protein is a member of a multigenic protein family. In mammals it consists of seven members (β, ε, η, γ, τ, ζ and σ) which act as adapter proteins involved in the regulation of a large number of signaling pathways [62,63] and in the maintenance of epithelial cell polarity [64]. It is interesting to note that this protein is frequently overexpressed in breast cancer [14].…”

Section: Mmp-2 Direct Interactorsmentioning

confidence: 99%

New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations

Cara¹,

Marabeti²,

Musso³

et al. 2018

Preprint

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Matrix metalloproteases (MMPS) are a family of well-known enzymes which operate prevalently in the extracellular domain, where they fulfil the function of remodeling the extracellular matrix. Within the about 26 family members, encoded by 24 genes in humans, MMP-2 and MMP-9, have been regarded as the primary responsibility for the basement membrane and pericellular ECM rearrangement. In cases of infiltrating carcinomas, which arise from the epithelial tissues of a gland or of an internal organ, a marked alteration of the expression and the activity levels of both MMPs is known to occur. Present investigation represents the continuation and upgrading of our previous studies, now focusing on the occurrence and intensity levels of MMP-2 and -9, and their proteomic correlations, in a cohort of 80 breast cancer surgical tissues.

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“…The1 4-3-3 adapter proteins are an especially interesting protein class because of their interaction with several hundred protein partners,m any of which are involved in human disease, [19,20] including the breast-cancer target, estrogen receptor a (ERa). [21] They are dimerized proteins that typically bind their partner proteins through short, phosphorylated motifs [22] either at two single-motif binding sites or at atandem binding site,which greatly enhances the binding affinity.…”

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confidence: 99%

“…[17,18] Protein assemblies frequently employ multivalent binding events,but the switching of this multivalency, for example between mono-and bivalent states,i sn ot readily modulated by classical small molecules. Thedistinctive structural and functional features of synthetic supramolecular systems are generating new modes for modulating such protein assemblies that act in an orthogonal manner to classical small-molecule modulation.[18] Within this context, the generation of multivalent supramolecular protein assemblies and their structural elucidation requires urgent attention.The1 4-3-3 adapter proteins are an especially interesting protein class because of their interaction with several hundred protein partners,m any of which are involved in human disease, [19,20] including the breast-cancer target, estrogen receptor a (ERa).[21] They are dimerized proteins that typically bind their partner proteins through short, phosphorylated motifs [22] either at two single-motif binding sites or at atandem binding site,which greatly enhances the binding affinity.[23] Whereas PPIs with the 14-3-3 monomer can be modulated by natural products, [23] peptide derivatives, [22,24,25] synthetic molecules, [26] or supramolecular ligands, [3] molecular approaches to control the valency of 14-3-3-protein complexes are currently absent. Therefore,werationally designed abinary bivalent supramolecular assembly platform based on cucurbit[8]uril and dimeric adapter protein 14-3-3.…”

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A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14‐3‐3

et al. 2017

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Interactions between proteins frequently involve recognition sequences based on multivalent binding events. Dimeric 14-3-3 adapter proteins are aprominent example and typically bind partner proteins in aphosphorylation-dependent mono-or bivalent manner.H erein we describe the development of ac ucurbit [8]uril (Q8)-based supramolecular system, which in conjunction with the 14-3-3 protein dimer acts as abinary and bivalent protein assembly platform. We fused the phenylalanine-glycine-glycine (FGG) tripeptide motif to the N-terminus of the 14-3-3-binding epitope of the estrogen receptor a (ERa)f or selective binding to Q8. Q8-induced dimerization of the ERa epitope augmented its affinity towards 14-3-3 through ab inary bivalent binding mode.T he crystal structure of the Q8-induced ternary complex revealed molecular insight into the multiple supramolecular interactions between the protein, the peptide,a nd Q8.Supramolecular systems have shown great potential for the modulation of biomolecular assemblies. [1][2][3][4] Theselective and strong recognition of peptide and protein elements in particular by synthetic supramolecular host molecules has attracted significant attention. [5][6][7][8][9][10] These prior studies have laid the foundation for supramolecularly controlled protein dimerization, functioning, and assembly orthogonal to natural recognition and switching events. [3,[11][12][13] Notable examples include the dimerization of carbonic anhydrase by the use of as ynthetic foldamer platform [14,15] and the cucurbit[8]uril (Q8)-mediated functional reconstitution of as plit luciferase enzyme.[16] Thes tudy and modulation of protein-protein interactions (PPIs) is one of the most progressive areas of chemical biology and important for both fundamental research and drug discovery. [17,18] Protein assemblies frequently employ multivalent binding events,but the switching of this multivalency, for example between mono-and bivalent states,i sn ot readily modulated by classical small molecules. Thedistinctive structural and functional features of synthetic supramolecular systems are generating new modes for modulating such protein assemblies that act in an orthogonal manner to classical small-molecule modulation.[18] Within this context, the generation of multivalent supramolecular protein assemblies and their structural elucidation requires urgent attention.The1 4-3-3 adapter proteins are an especially interesting protein class because of their interaction with several hundred protein partners,m any of which are involved in human disease, [19,20] including the breast-cancer target, estrogen receptor a (ERa).[21] They are dimerized proteins that typically bind their partner proteins through short, phosphorylated motifs [22] either at two single-motif binding sites or at atandem binding site,which greatly enhances the binding affinity.[23] Whereas PPIs with the 14-3-3 monomer can be modulated by natural products, [23] peptide derivatives, [22,24,25] synthetic molecules, [26] or supramolecular ligands, [3] molecul...

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The role of the 14-3-3 protein family in health, disease, and drug development

Cited by 223 publications

References 63 publications

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations

A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14‐3‐3

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