The C-terminal domain of the antiamyloid chaperone DNAJB6 binds to amyloid-β peptide fibrils and inhibits secondary nucleation

Österlund, Nicklas; Frankel, Rebecca; Carlsson, Andreas; Thacker, Dev; Karlsson, Maja; Matus, Vanessa; Gräslund, Astrid; Emanuelsson, Cecilia; Linse, Sara

doi:10.1016/j.jbc.2023.105317

Cited by 4 publications

(5 citation statements)

References 66 publications

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“…This suggests its potential relevance in the biological setting and potential as a drug target, given the limited number of known secreted chaperones [64]. Importantly, the fact that S100B, like DNAJB6 [65,66] and the Brichos domain [67][68][69], are able to inhibit Aβ42 secondary nucleation, which is the main route to generate toxic oligomers, makes this type of proteins attractive inspirations for translational AD therapies [70][71][72].…”

Section: Discussionmentioning

confidence: 99%

Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer’s Disease Pathology

Coelho,

De Benedictis,

Sauer

et al. 2024

IJMS

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Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer’s Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aβ aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aβ binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aβ toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B.

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Section: Discussionmentioning

confidence: 99%

Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer’s Disease Pathology

Coelho,

De Benedictis,

Sauer

et al. 2024

IJMS

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“…For example, it plays a role of an endogenous chaperone for huntingtin neuronal protein [121]. Being able to successfully suppress aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins [122,123], DnaJB6 is designated as the antiamyloid chaperone, which is also capable of binding to the amyloid-β peptide fibrils and inhibiting secondary nucleation [124]. Furthermore, this chaperone is related to the biogenesis of the interphase nuclear pore complex (NPCs), binds to phenylalanine-glycine-rich nucleoporins (FG-Nups), and prevents their aggregation in cells and in vitro [125].…”

Section: Charged Multivesicular Body Protein 4b (Chmp4b Uniprot Id: Q...mentioning

confidence: 99%

Intrinsic Disorder in the Host Proteins Entrapped in the Rabies Virus Particles

Ashraf,

Uversky

2024

Preprint

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Proteomic analysis of purified rabies virus (RABV) revealed 47 entrapped host proteins within viral particles. Out of these, 11 proteins were highly disordered. Our study was particularly focused on five of the RABV-entrapped mouse proteins with the highest levels of disorder, Neuromodulin, Chmp4b, DnaJB6, Vps37B, and Wasl. We extensively utilized bioinformatics tools, such as FuzDrop, D2P2, UniProt, RIDAO, STRING, AlphaFold, and ELM for comprehensive analysis of the intrinsic disorder propensity of these proteins. Our analysis suggested that these disordered host proteins might play a significant role in facilitating the rabies virus pathogenicity, immune system evasion, and the development of the antiviral drug resistance. Our study highlighted the complex interaction of the virus with its host, with the focus on how the intrinsic disorder can play a crucial role in virus pathogenic processes and suggested that these intrinsically disordered proteins (IDPs) and disorder-related host interactions can also be a potential target for the therapeutic strategies.

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“…For example, it plays the role of an endogenous chaperone for huntingtin neuronal protein [ 117 ]. Being able to successfully suppress the aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins [ 118 , 119 ], DnaJB6 is designated as the antiamyloid chaperone, which is also capable of binding to the amyloid-β peptide fibrils and inhibiting secondary nucleation [ 120 ]. Furthermore, this chaperone is related to the biogenesis of the interphase nuclear pore complex (NPC), binds to phenylalanine–glycine-rich nucleoporins (FG-Nups), and prevents their aggregation in cells and in vitro [ 121 ].…”

Section: Appendix A1 Functional Intrinsic Disorder In the Most Disord...mentioning

confidence: 99%

Intrinsic Disorder in the Host Proteins Entrapped in Rabies Virus Particles

Ashraf,

Uversky

2024

Viruses

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A proteomics analysis of purified rabies virus (RABV) revealed 47 entrapped host proteins within the viral particles. Out of these, 11 proteins were highly disordered. Our study was particularly focused on five of the RABV-entrapped mouse proteins with the highest levels of disorder: Neuromodulin, Chmp4b, DnaJB6, Vps37B, and Wasl. We extensively utilized bioinformatics tools, such as FuzDrop, D2P2, UniProt, RIDAO, STRING, AlphaFold, and ELM, for a comprehensive analysis of the intrinsic disorder propensity of these proteins. Our analysis suggested that these disordered host proteins might play a significant role in facilitating the rabies virus pathogenicity, immune system evasion, and the development of antiviral drug resistance. Our study highlighted the complex interaction of the virus with its host, with a focus on how the intrinsic disorder can play a crucial role in virus pathogenic processes, and suggested that these intrinsically disordered proteins (IDPs) and disorder-related host interactions can also be a potential target for therapeutic strategies.

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The C-terminal domain of the antiamyloid chaperone DNAJB6 binds to amyloid-β peptide fibrils and inhibits secondary nucleation

Cited by 4 publications

References 66 publications

Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer’s Disease Pathology

Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer’s Disease Pathology

Intrinsic Disorder in the Host Proteins Entrapped in the Rabies Virus Particles

Intrinsic Disorder in the Host Proteins Entrapped in Rabies Virus Particles

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