The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

Sbardella, Diego; Tundo, Grazia R.; Coletta, Andrea; Marcoux, Julien; Koufogeorgou, Efthymia Ioanna; Ciaccio, Chiara; Santoro, Anna Maria; Milardi, Danilo; Grasso, Giuseppe; Cozza, Paola; Bousquet, Marie‐Pierre; Marini, Stefano; Coletta, Massimo

doi:10.1007/s00018-018-2807-y

Cited by 40 publications

(44 citation statements)

References 67 publications

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“…[65] Moreover, the 19S particle, as well as other 20S activators, induces complex conformational changes that allosterically facilitates substrate translocation and hydrolysis in the catalytic β-subunits. [66][67][68][69] All known types of RPs, including 19S, PA200 and PA28 include an HbYX (hydrophobic, Hb; Tyrosine, Y; any amino acid, X) motif which plays a key role in steering RPs/20S assembly and in promoting gate opening. [37,70,71] For this reason, many peptides harnessing the HbYX motif including i) the activating loop and C-terminus of PA28, [72] the cathelicidin antibacterial peptide PR39, [73] the octa peptide Arg(8) [74] and the HIV-1 Tat protein, [75] were shown to be allosteric 20S activators.…”

Section: Discussionmentioning

confidence: 99%

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

et al. 2019

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Proteasome malfunction parallels abnormal amyloid accumulation in Alzheimer's Disease (AD). Here we scrutinize a small library of pyrazolones by assaying their ability to enhance proteasome activity and protect neuronal cells from amyloid toxicity. Tube tests evidenced that aminopyrine and nifenazone behave as 20S proteasome activators. Enzyme assays carried out on an "open gate" mutant (α3ΔN) proteasome demonstrated that aminopyrine activates proteasome through binding the α-ring surfaces and influencing gating dynamics. Docking studies coupled with STD-NMR experiments showed that H-bonds and π-π stacking interactions between pyrazolones and the enzyme play a key role in bridging α1 to α2 and, alternatively, α5 to α6 subunits of the outer α-ring. Aminopyrine and nifenazone exhibit neurotrophic properties and protect differentiated human neuroblastoma SH-SY5Y cells from β-amyloid (Aβ) toxicity. ESI-MS studies confirmed that aminopyrine enhances Aβ degradation by proteasome in a dosedependent manner. Our results suggest that some pyrazolones and, in particular, aminopyrine are promising compounds for the development of proteasome activators for AD treatment.

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Section: Discussionmentioning

confidence: 99%

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

et al. 2019

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“…Structure-activity relationships (SARs) studies pointed out the complex interplay existing between structural flexibility and charge in the regulation of the inhibitory potency of Tat-derived peptides [ 33 ]. Ionic interactions are also at the base of the allosteric modulation of the h20S catalytic activities by insulin degrading enzyme (IDE) [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

Santoro

D’Urso

Cunsolo

et al. 2020

IJMS

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The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural “key code” present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators.

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“…The chaperone or proteasome systems are possible candidates to be involved in this phenomenon [59]. Actually, previous studies had shown that IDE will interact with 20S proteasome and modulate its proteolytic activity [60]. Our results showed that TC treatment could not only enhance the expression of IDE but also increase the proteasome expressions of 20S (PSMA3) and 19S (PSMC3) subunits.…”

Section: Plos Onementioning

confidence: 55%

Thermal cycling protects SH-SY5Y cells against hydrogen peroxide and β-amyloid-induced cell injury through stress response mechanisms involving Akt pathway

et al. 2020

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Neurodegenerative diseases (NDDs) are becoming a major threat to public health, according to the World Health Organization (WHO). The most common form of NDDs is Alzheimer's disease (AD), boasting 60-70% share. Although some debates still exist, excessive aggregation of β-amyloid protein (Aβ) and neurofibrillary tangles has been deemed one of the major causes for the pathogenesis of AD. A growing number of evidences from studies, however, have suggested that reactive oxygen species (ROS) also play a key role in the onset and progression of AD. Although scientists have had some understanding of the pathogenesis of AD, the disease still cannot be cured, with existing treatment only capable of providing a temporary relief at best, partly due to the obstacle of blood-brain barrier (BBB). The study was aimed to ascertain the neuroprotective effect of thermal cycle hyperthermia (TC-HT) against hydrogen peroxide (H 2 O 2) and Aβ-induced cytotoxicity in SH-SY5Y cells. Treating cells with this physical stimulation beforehand significantly improved the cell viability and decreased the ROS content. The underlying mechanisms may be due to the activation of Akt pathway and the downstream antioxidant and prosurvival proteins. The findings manifest significant potential of TC-HT in neuroprotection, via inhibition of oxidative stress and cell apoptosis. It is believed that coupled with the use of drugs or natural compounds, this methodology can be even more effective in treating NDDs.

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The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

Cited by 40 publications

References 67 publications

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

Thermal cycling protects SH-SY5Y cells against hydrogen peroxide and β-amyloid-induced cell injury through stress response mechanisms involving Akt pathway

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