Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

Landreh, Michael; Rising, Anna; Presto, Jenny; Jörnvall, Hans; Johansson, Jan

doi:10.1074/jbc.r115.653097

Cited by 34 publications

(22 citation statements)

References 90 publications

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“…However, structural studies have provided important clues to understanding these pathologies. These studies have revealed common architectural features of amyloids that enable the rational design of inhibitors , discovered correlations between structural features of benign precursor proteins and corresponding amyloids and their associated pathologies , and unravelled how chaperones inhibit amyloid formation ; such findings also guide drug design that can ultimately yield clinically approved compounds for the treatment of amyloid disorders . Although we are still far from being able to cure patients with these devastating disorders, these significant advances allow us to look forward to a future in which much‐needed treatments are available.…”

Section: Discussionmentioning

confidence: 99%

The formation, function and regulation of amyloids: insights from structural biology

et al. 2016

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Amyloid diseases are characterized by the accumulation of insoluble, β-strand-rich aggregates. The underlying structural conversions are closely associated with cellular toxicity, but can also drive the formation of functional protein assemblies. In recent years, studies in the field of structural studies have revealed astonishing insights into the origins, mechanisms and implications of amyloid formation. Notably, high-resolution crystal structures of peptides in amyloid-like fibrils and prefibrillar oligomers have become available despite their challenging chemical nature. Nuclear magnetic resonance spectroscopy has revealed that dynamic local polymorphisms in the benign form of the prion protein affect the transformation into amyloid fibrils and the transmissibility of prion diseases. Studies of the structures and interactions of chaperone proteins help us to understand how the cellular proteostasis network is able to recognize different stages of aberrant protein folding and prevent aggregation. In this review, we will focus on recent developments that connect the different aspects of amyloid biology and discuss how understanding the process of amyloid formation and the associated defence mechanisms can reveal targets for pharmacological intervention that may become the first steps towards clinically viable treatment strategies.

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Section: Discussionmentioning

confidence: 99%

The formation, function and regulation of amyloids: insights from structural biology

et al. 2016

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“…As Fig 1 illustrates, chaperones together with co-chaperones dynamically participate in the interactome (nodes with blue border). This finding was, more or less, an expected phenomenon, since molecular chaperones are molecules dedicated to suppress amyloid formation [91, 92] and usually have many interactors [93]. The expert review, by Yerbury & Kumita, presents an extended group of amyloid-specific chaperones and discusses their implications [94].…”

Section: Resultsmentioning

confidence: 99%

The amyloid interactome: Exploring protein aggregation

et al. 2017

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Protein-protein interactions are the quintessence of physiological activities, but also participate in pathological conditions. Amyloid formation, an abnormal protein-protein interaction process, is a widespread phenomenon in divergent proteins and peptides, resulting in a variety of aggregation disorders. The complexity of the mechanisms underlying amyloid formation/amyloidogenicity is a matter of great scientific interest, since their revelation will provide important insight on principles governing protein misfolding, self-assembly and aggregation. The implication of more than one protein in the progression of different aggregation disorders, together with the cited synergistic occurrence between amyloidogenic proteins, highlights the necessity for a more universal approach, during the study of these proteins. In an attempt to address this pivotal need we constructed and analyzed the human amyloid interactome, a protein-protein interaction network of amyloidogenic proteins and their experimentally verified interactors. This network assembled known interconnections between well-characterized amyloidogenic proteins and proteins related to amyloid fibril formation. The consecutive extended computational analysis revealed significant topological characteristics and unraveled the functional roles of all constituent elements. This study introduces a detailed protein map of amyloidogenicity that will aid immensely towards separate intervention strategies, specifically targeting sub-networks of significant nodes, in an attempt to design possible novel therapeutics for aggregation disorders.

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“…Small Hsps (12-42 KDa) do not require ATP since they usually function as holdases and assist other proteins in Hsp chaperone complex [41]. Hsp104 is part of proteostasis network which regulates prion assembly in yeast, Hsp110 is its human counterpart which facilitates chaperone function of Hsp70 and Hsp40 [43]. Hsp90 and its co-chaperones interact with tau and a close control on their interaction can cause the oligomers to turn into benign species instead of toxic aggregates [44].…”

Section: Heat Shock Proteinsmentioning

confidence: 99%

“…Some inherently amyloidogenic proteins such as PrP, hTTR and BRICHOS-domain containing proteins can paradoxically also inhibit aggregation of other amyloids. BRICHOS-domain containing protein ITM2B (Bri2) is a CNS membrane protein which shows chaperone functions for amyloids by binding to tyrosine and other charged residues [43]. Tetrameric form of Transthyretin (TTR) can also prevent aggregation of amyloid oligomers [44].…”

Section: Non-proteolytic Amyloid Chaperonesmentioning

confidence: 99%

Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer’s Disease

Sharma¹,

Pervushin²

2019

Amyloid Diseases

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This chapter attempts to explore protective role of chaperone proteins in the neurodegenerative diseases caused by amyloidosis. These chaperones prevent amyloid pathology either directly, through chemical interactions with amyloidogenic species to mediate their refolding, solubilization and degradation, or indirectly, by scavenging reactive oxygen species produced as by-products of amyloid aggregation. Here we focus on structural and morphological changes during aggregation of amyloids which have been identified using Nuclear magnetic resonance spectroscopy, X-ray crystallography, Electron microscopy, Atomic force microscopy and other biophysical techniques as well as interactions between chaperone proteins and amyloid moieties. Non-proteolytic chaperones mediate amyloid clearance and metabolism through conformational changes due to proximity binding. In this chapter, we delineate these interactions as well as the molecular mechanism of chaperones used to sequester ROS products of amyloidosis with focus on amyloid-β peptides associated with the Alzheimer's disease.

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Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

Cited by 34 publications

References 90 publications

The formation, function and regulation of amyloids: insights from structural biology

The formation, function and regulation of amyloids: insights from structural biology

The amyloid interactome: Exploring protein aggregation

Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer’s Disease

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