(Dis)Solving the problem of aberrant protein states

Fare, Charlotte M.; Shorter, James

doi:10.1242/dmm.048983

Cited by 26 publications

(37 citation statements)

References 84 publications

(145 reference statements)

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“…With the goal of generating a rationally designed, non-amyloidogenic variant of PNT3, we carried out a bioinformatic analysis. Taking into account the ability of prion-like domains (PLDs) (i.e., IDRs enriched in Asn and Gln residues) to drive fibrillation [38,41,[95][96][97][98], we first analyzed the PNT3 sequence using various PLD predictors including LPS, PAPA, PLAAC, and PrionW (see [99] and references therein cited). No PLD was found within the PNT3 sequence, indicating that the sequence determinants that drive the fibrillation of PNT3 are distinct from those of typical PLDs.…”

Section: Rational Design Of a Pnt3 Variant With A Hampered Ability To Form Amyloid-like Fibrilsmentioning

confidence: 99%

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

et al. 2021

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Henipaviruses are BSL-4 zoonotic pathogens responsible in humans for severe encephalitis. Their V protein is a key player in the evasion of the host innate immune response. We previously showed that the Henipavirus V proteins consist of a long intrinsically disordered N-terminal domain (NTD) and a β-enriched C-terminal domain (CTD). These terminals are critical for V binding to DDB1, which is a cellular protein that is a component of the ubiquitin ligase E3 complex, as well as binding to MDA5 and LGP2, which are two host sensors of viral RNA. Here, we serendipitously discovered that the Hendra virus V protein undergoes a liquid-to-hydrogel phase transition and identified the V region responsible for this phenomenon. This region, referred to as PNT3 and encompassing residues 200–310, was further investigated using a combination of biophysical and structural approaches. Congo red binding assays, together with negative-staining transmisison electron microscopy (TEM) studies, show that PNT3 forms amyloid-like fibrils. Fibrillation abilities are dramatically reduced in a rationally designed PNT3 variant in which a stretch of three contiguous tyrosines, falling within an amyloidogenic motif, were replaced by three alanines. Worthy to note, Congo red staining experiments provided hints that these amyloid-like fibrils form not only in vitro but also in cellula after transfection or infection. The present results set the stage for further investigations aimed at assessing the functional role of phase separation and fibrillation by the Henipavirus V proteins.

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Section: Rational Design Of a Pnt3 Variant With A Hampered Ability To Form Amyloid-like Fibrilsmentioning

confidence: 99%

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

et al. 2021

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“…Upregulation of transcripts of both ATP-dependent and -independent HSP mRNAs (Fig. 4B, C) might implicate a cellular strategy wherein a cell can employ these proteins in clearing aggregates distinctly and more efficiently (Fare and Shorter, 2021); some of these genes may also be involved in long-term stress adaptation (Bijlsma and Loeschcke, 2005; De Bruijn, 2016).…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Response to Oxidative Stress Is Independent of Stress-Granule Formation

Singh

Kandi

Jayaprakashappa

et al. 2021

Preprint

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Cells respond to stress with translational arrest, robust transcriptional changes, and transcription-independent formation of mRNP assemblies termed stress granules (SGs). Despite considerable interest in the role of SGs in oxidative, unfolded-protein, and viral stress responses, whether and how SGs contribute to stress-induced transcription has not been rigorously examined. To address this issue, we characterized transcriptional changes in Drosophila S2 cells induced by acute oxidative-stress and assessed how these were altered under conditions that disrupted SG assembly. Sodium-arsenite stress for 3 hours predominantly resulted in the induction or upregulation of stress-responsive mRNAs whose levels peaked during cell recovery after stress cessation. The stress-transcriptome is enriched in mRNAs coding for protein chaperones, including HSP70 and low molecular-weight heat shock proteins, glutathione transferases, and several non-coding RNAs. Oxidative stress also induced prominent cytoplasmic stress granules that disassembled 3-hours after stress cessation. As expected, RNAi-mediated knockdown of the conserved G3BP1/ Rasputin protein inhibited stress-granule assembly. However, this disruption had no significant effect on the stress-induced transcriptional response or stress-induced translational arrest. Thus, SG assembly and stress-induced effects on gene expression appear to be driven by distinctive signaling processes. We suggest that while SG assembly represents a fast, transient mechanism, the transcriptional response enables a slower, longer-lasting mechanism for adaptation to and recovery from cell stress.

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“…An activated disaggregase would promote this situation but, as reported for Hsp104, a strong activity could also unfold non-pathogenic proteins, and therefore be toxic, especially if the concentration of the target substrate protein(s) decreases [127]. It would also be desirable to enhance the activity of the specific chaperone-cochaperones combinations involved in the disaggregation of a specific substrate protein, a task that is far for being achieved for the human disaggregase and has started to be developed for Hsp104 [46,128]. This could be accomplished by engineering new chaperones/cochaperones that recognize certain substrates and/or by small molecules that favor specific interactions between the components of the disaggregase and activate the complex.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

Franco

Velasco-Carneros

Alvarez

et al. 2021

Cells

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Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.

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(Dis)Solving the problem of aberrant protein states

Cited by 26 publications

References 84 publications

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

The Transcriptional Response to Oxidative Stress Is Independent of Stress-Granule Formation

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

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