Modulation of 14-3-3/Phosphotarget Interaction by Physiological Concentrations of Phosphate and Glycerophosphates

Sluchanko, Nikolai N.; Chebotareva, Natalia A.; Gusev, Nikolai B.

doi:10.1371/journal.pone.0072597

Cited by 22 publications

(21 citation statements)

References 29 publications

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“…Inorganic phosphate and other phosphate-containing molecules can serve as regulators of 14-3-3/phosphate interactions. Inorganic phosphates induce dissociation of complexes formed by phosphorylated HspB6 and 14-3-3γ or 14-3-3ζ, [65]. 14-3-3 expression was observed in the valvular spongiosa in degenerated aortic disease and aorta specimens from patients with large vessel vasculitides [59,66].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Yu¹,

Kapur²,

Hamid³

et al. 2018

J Pharmacogenomics Pharmacoproteom

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Aortic valve stenosis is one of the most common valve diseases in the world for which there is currently no pharmacological treatment to prevent or halt disease progression. Recent genetic research has demonstrated a causal association between elevated blood levels of lipoprotein (a) (Lp (a)) and aortic valve calcification, however, the mechanisms by which Lp (a) contributes to aortic valve calcification and stenosis, is unknown. In the present study, we aimed at determining Lp (a)-induced changes in human aortic valve interstitial cells using an integrated bioinformatics approach. The Lp (a)-induced cellular pathways were analysed using microarray gene expression and proteomic data from non-stenotic human aortic valve interstitial cells. Lp (a) treatment induced osteogenic differentiation, extracellular remodeling, extracellular vesicles biogenesis, and apoptosis of human aortic valve interstitial cells. In particular, the Wnt/ β-catenin signalling pathway, a known calcification pathway contributing to aortic valve stenosis, was differentially expressed compared to non-treated cells. Lp (a) also induced the expression of 14-3-3 proteins known to regulate various signalling pathway relevant to aortic valve disease. Elucidating the mechanisms and molecular players that Lp (a) induces in the early stages of the disease to initiate aortic valve calcification could provide insight into potential pharmacological targets for the treatment of this debilitating disease.

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Section: Discussionmentioning

confidence: 99%

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Yu¹,

Kapur²,

Hamid³

et al. 2018

J Pharmacogenomics Pharmacoproteom

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“…Importantly, this anti‐aggregation activity of 14‐3‐3 is concentration‐dependent. In contrast to the main phosphopeptide‐binding function of 14‐3‐3 that is specifically dependent on electrostatic interactions , the chaperone‐like activity seems not to be inhibited by phosphate ions, as judged from the ability of 14‐3‐3 to prevent aggregation of different model proteins in buffers containing 50 m m phosphate . Moreover, the chaperone‐like activity of 14‐3‐3 seems not to be generally dependent on target protein phosphorylation, in contrast to the main phosphopeptide‐binding (adaptor) function of 14‐3‐3 (Fig.…”

Section: Chaperone‐like Activity Of 14‐3‐3 With Model Protein Substratesmentioning

confidence: 97%

“…However, as different positions contribute to the binding affinity differently, some deviations from this binding rule are also known . Importantly, phosphorylation‐dependent binding to 14‐3‐3 relies on electrostatic interactions and can be appreciably inhibited by millimolar concentrations of inorganic phosphate or sulfate anions that compete with the phosphate moiety of phosphopeptide partners for 14‐3‐3 binding .…”

Section: ‐3‐3 Structure and Functionmentioning

confidence: 99%

Moonlighting chaperone‐like activity of the universal regulatory 14‐3‐3 proteins

Sluchanko

Gusev

2017

The FEBS Journal

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The ubiquitous eukaryotic 14‐3‐3 proteins coordinate multiple cellular processes due to their well‐known regulatory function, which is based on specific recognition of phosphorylated motifs in their partners. In this context, 14‐3‐3 proteins have been called ‘chaperones’. Although in the classical meaning this is not fully correct, recent studies have revealed that they can indeed be an integral part of the protein quality control system, as they (a) display ATP‐independent anti‐aggregation (‘holdase’) activity, similar to that of the unrelated small heat shock proteins, (b) assist in clearing misfolded proteins by directing them to proteasomes or aggresomes, (c) cooperate with classical chaperones for substrate refolding, and also (d) are associated with neurodegenerative disorders by affecting aggregation of tau, prion protein, α‐synuclein, huntingtin, etc. Importantly, these activities are usually independent of substrate phosphorylation and therefore should be considered as distinct, ‘moonlighting’ functions of 14‐3‐3 proteins that mimic and complement the functions of dedicated molecular chaperones. Although the precise mechanism of this activity is still unknown, it has been shown that it is not dependent on the unstructured C‐terminal region or the amphipathic phosphopeptide‐binding groove. However, since disassembly of 14‐3‐3 dimers significantly increases their chaperone‐like activity, the dimer interface, located in the N terminus, possessing a high disorder propensity and pronounced hydrophobicity, is likely to be involved. Various factors affecting the oligomeric status of 14‐3‐3 proteins can thus regulate the balance between regulatory phosphomotif binding and genuine chaperone‐like activity. Understanding the latter mode of 14‐3‐3 functioning is fundamental to defining the underlying molecular mechanisms for a range of human disorders.

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“…This interaction was again strictly dependent on HspB6 phosphorylation and binding of phosphorylated HspB6 induced stabilization of dimer-defi cient mutant of 14-3-3 . Interaction of HspB6 and 14-3-3 is modulated by physiological concentrations of phosphate (Sluchanko et al 2013 ) and therefore oscillation of phosphate concentration appearing in the course of muscle contraction can affect interaction of HspB6 and 14-3-3 ( Fig. 9.2 ).…”

Section: Hspb6 and Regulation Of Smooth Muscle Contractionmentioning

confidence: 99%

HSPB6 (Hsp20) as a Versatile Molecular Regulator

Sudnitsyna

Sluchanko

Gusev

2015

Heat Shock Proteins

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HspB6 (Hsp20) is a member of the large family of human small heat shock proteins. In contrast to other human small heat shock proteins (HspB1, HspB5) forming large oligomers, HspB6 predominantly forms stable dimers which tend to self-association. HspB6 is ubiquitously expressed in practically all human tissues, undergoes posttranslational modifi cations (such as phosphorylation and acetylation) and forms heterooligomeric complexes with two other human small heat shock proteins, HspB1 and HspB5. Possessing chaperone-like activity, HspB6 prevents aggregation of amyloid-β and α-synuclein, decreases cytotoxicity induced by accumulation of amyloids and, interacting with Bag3, modulates autophagosomal degradation of misfolded proteins. HspB6 protects cardiomyocytes from ischemia/reperfusion injuries, prevents cardiac hypertrophy and, possessing antiapoptotic activity, protects cardiomyocytes from different unfavorable conditions. Phosphorylation of HspB6 catalyzed by cyclic nucleotide-dependent protein kinases induces relaxation of different smooth muscle. Exact molecular mechanism underlying relaxation effect of phosphorylated HspB6 in smooth muscle remains enigmatic, but seems to be dependent on the remodeling of actin cytoskeleton. HspB6 is not a genuine actin-binding protein, but interacting with universal adapter protein 14-3-3 seems to be able indirectly affect activity of certain regulatory actin-binding proteins thus inducing cytoskeleton remodeling. Penetrating phosphorylated peptides of HspB6 were successfully used for relaxation of airway smooth muscle and prevention of vasospasm in human blood vessels. Full-size HspB6 and its short peptides modulate platelet aggregation. Versatility of HspB6 is awaiting further investigation, however it can be at least partially explained by the ability of phosphorylated HspB6 to interact with the universal adapter protein 14-3-3 and to displace different target proteins from their complexes with 14-3-3. This displacement may result in modulation of target protein activity and consequently can induce multiple and diverse effects.

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Modulation of 14-3-3/Phosphotarget Interaction by Physiological Concentrations of Phosphate and Glycerophosphates

Cited by 22 publications

References 29 publications

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Gene Expression and Proteomic Profiling of Lp (a)-Induced Signalling Pathways in Human Aortic Valve Interstitial Cells

Moonlighting chaperone‐like activity of the universal regulatory 14‐3‐3 proteins

HSPB6 (Hsp20) as a Versatile Molecular Regulator

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