Recombinant Bri3 BRICHOS domain is a molecular chaperone with effect against amyloid formation and non-fibrillar protein aggregation

Poska, Helen; Leppert, Axel; Tigro, Helene; Zhong, Xueying; Kaldmäe, Margit; Nilsson, Hans C.; Hebert, Hans; Chen, Gefei; Johansson, Jan

doi:10.1038/s41598-020-66718-y

Cited by 18 publications

(24 citation statements)

References 48 publications

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“…However, ImmuMethy revealed that cg15127563, which is found within the ITM2C gene (integral membrane protein 2C, also known as BRI3), is a novel differential methylation site with elevated methylation levels in PD patients ( Figure 5 ). In a recent study, recombinant BRI3 protein was found to function as a molecular chaperone to inhibit amyloid formation and nonfibrillar protein aggregation ( 22 ). However, whether this CpG site is involved in the development of neurodegenerative diseases awaits further investigation.…”

Section: Resultsmentioning

confidence: 99%

ImmuMethy, a database of DNA methylation plasticity at a single cytosine resolution in human blood and immune cells

Song

Wang

2022

Database

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Differential DNA methylation is a feature of numerous physiological and pathological processes. However, the extent to which single-base cytosine methylation modifies cellular responses to various stimuli has not been well characterized. In this study, we carried out a systematic analysis of methylome data derived from human blood and immune cells and constructed the ImmuMethy database. ImmuMethy allows interrogation of DNA methylation plasticity (MPL) at the single cytosine level. MPL, which refers to the variability of DNA methylation, is quantitatively measured in multiple ways, such as quartiles and standard deviations. ImmuMethy comprises over 36 000 samples from the Human Methylation450 and MethylationEPIC BeadChips platforms and provides multiple applications, such as an overview of methylation status and plasticity, differential methylation analysis, identification of methylation markers and sample stratification. An analysis of all datasets revealed that DNA methylation is generally stable, with minimal changes in beta values. This further supports the characteristics of DNA methylation homeostasis. Based on the beta value distribution, we identified three types of methylation sites: methylation tendency sites, unmethylation tendency sites and dual tendency or nonbiased methylation sites. These sites represent different methylation tendentiousness of DNA methylation across samples. The occurrence of multiple methylation tendencies in a site means split methylation, which generally corresponds to high MPL. Inverted methylation tendencies from methylation tendency sites to unmethylation tendency sites, or vice versa, represent strong differential methylation in response to conditions. All these sites can be identified in ImmuMethy, making it a useful tool for omics-based data-driven knowledge discovery. Database URL: http://immudb.bjmu.edu.cn/immumethy/

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Section: Resultsmentioning

confidence: 99%

ImmuMethy, a database of DNA methylation plasticity at a single cytosine resolution in human blood and immune cells

Song

Wang

2022

Database

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“…In contrast to Bri2, the overall levels of Bri3 are shown to be decreased in AD, although the deposition with the amyloid plaques is similar for both Bri2 and Bri3 [202]. BRICHOS from both Bri2 and Bri3 interact with Aβ in neurons and inhibit Aβ fibrillization in vitro, but Bri3 shows less efficiency compared to Bri2 [202,203], suggesting a different role for Bri2 and Bri3 BRICHOS in Aβ pathology.…”

Section: Brichosmentioning

confidence: 90%

“…Among the BRICHOS proteins, the Bri2 and Bri3 of the BRI family play a significant role in the prevention of neurodegenerative diseases [47,193,202,203]. These proteins are highly expressed in the brain.…”

Section: Brichosmentioning

confidence: 99%

“…Particularly, Bri2 BRICHOS monomers potently prevent Aβ-induced neuronal network toxicity, while dimers strongly suppress Aβ fibril formation, and higher molecular weight-oligomers efficiently inhibit non-fibrillar protein aggregation [214]. It has been shown also that Bri3 BRICHOS forms more and larger oligomers and prevents non-fibrillar protein aggregation better than Bri2 BRICHOS oligomers, which explains its lower efficiency in suppressing Aβ42 fibrilization compared to Bri2 BRICHOS [203].…”

Section: Brichosmentioning

confidence: 99%

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Endogenous Human Proteins Interfering with Amyloid Formation

et al. 2022

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Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

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“…Interestingly, for the BRICHOS domains studied so far, the ability to suppress amorphous protein aggregation, the canonical molecular chaperone function, is not coupled to the ability to prevent amyloid fibril formation or toxicity. ProSP-C BRICHOS essentially lacks activity against amorphous protein aggregation, while Bri2 and Bri3 BRICHOS inhibit both fibrillar and non-fibrillar aggregation (32,34). We could recently explain the basis for this discrepancy by showing that the canonical chaperone activity to suppress amorphous protein aggregation is determined by specific loop segments in BRICHOS, while the activity against amyloid formation is independent of these segments (Chen et al, submitted for publication).…”

Section: Introductionmentioning

confidence: 99%

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

Chen

Andrade-Talavera

Zhong

et al. 2021

Preprint

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Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but the respective mechanisms are not fully understood. The BRICHOS domain constitutes a disease-associated small heat shock protein-like chaperone family, with activities against both amyloid toxicity and amorphous protein aggregation. Here, we show that the activity of two BRICHOS domain families against Alzheimer’s disease associated amyloid-β neurotoxicity to mouse hippocampi in vitro depends on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The conserved Asp in its ionized state promotes structural flexibility of the BRICHOS domain and has a pKa value between pH 6.0–7.0, suggesting that chaperone effects against amyloid toxicity can be affected by physiological pH variations. Finally, the Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families and animal species, indicating independent evolution of molecular chaperone activities against amyloid fibril formation and non-fibrillar amorphous protein aggregation.

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Recombinant Bri3 BRICHOS domain is a molecular chaperone with effect against amyloid formation and non-fibrillar protein aggregation

Cited by 18 publications

References 48 publications

ImmuMethy, a database of DNA methylation plasticity at a single cytosine resolution in human blood and immune cells

ImmuMethy, a database of DNA methylation plasticity at a single cytosine resolution in human blood and immune cells

Endogenous Human Proteins Interfering with Amyloid Formation

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

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