Dissociation from the Oligomeric State Is the Rate-limiting Step in Fibril Formation by κ-Casein

Ecroyd, Heath; Koudelka, Thomas; Thorn, David C.; Williams, Danielle M.; Devlin, Glyn L.; Hoffmann, Peter; Carver, John A.

doi:10.1074/jbc.m709928200

Cited by 79 publications

(143 citation statements)

References 46 publications

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“…Consistent with these data, the fibrilforming region of unstructured κ-casein is in the middle of the protein (Ecroyd et al 2008). Likewise, the crucial fibrilforming residues of amyloid β (Glu11 to Ala21) are in the middle of the peptide (Serpell 2000).…”

Section: The N-and C-terminal Flanking Regions In Shspssupporting

confidence: 74%

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Carver

Grosas

Ecroyd

et al. 2017

Cell Stress and Chaperones

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Small heat-shock proteins (sHsps), such as αB-crystallin, are one of the major classes of molecular chaperone proteins. In vivo, under conditions of cellular stress, sHsps are the principal defence proteins that prevent large-scale protein aggregation. Progress in determining the structure of sHsps has been significant recently, particularly in relation to the conserved, central and β-sheet structured α-crystallin domain (ACD). However, an understanding of the structure and functional roles of the N-and C-terminal flanking regions has proved elusive mainly because of their unstructured and dynamic nature. In this paper, we propose functional roles for both flanking regions, based around three properties: (i) they act in a localised crowding manner to regulate interactions with target proteins during chaperone action, (ii) they protect the ACD from deleterious amyloid fibril formation and (iii) the flexibility of these regions, particularly at the extreme C-terminus in mammalian sHsps, provides solubility for sHsps under chaperone and nonchaperone conditions. In the eye lens, these properties are highly relevant as the crystallin proteins, in particular the two sHsps αA-and αB-crystallin, are present at very high concentrations.

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Section: The N-and C-terminal Flanking Regions In Shspssupporting

confidence: 74%

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Carver

Grosas

Ecroyd

et al. 2017

Cell Stress and Chaperones

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“…As well, when the rate of α-synuclein fibril formation is increased through the addition of dextran (which acts as a molecular crowding agent), the effectiveness of αB-crystallin as a chaperone decreases [93]. Moreover, we have previously suggested that the intermediate formed during the fibril formation of κ-casein is very short lived compared to other proteins that form fibrils through the typical nucleation-dependent mechanism [109]. This may, at least in part, explain why comparatively high molar ratios of αB-crystallin are required to inhibit fibril formation by κ-casein compared to other systems which have been studied (i.e.…”

Section: Shsps and The Aβ Peptidesmentioning

confidence: 99%

Crystallin proteins and amyloid fibrils

Ecroyd

Carver

2008

Cell. Mol. Life Sci.

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Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, alpha-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of alpha B-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials. Improper protein folding (misfolding) can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The major lens protein, α-crystallin, is a member of the small heat-shock protein (sHsp) family of intracellular molecular chaperone proteins that prevent protein aggregation. Whilst the chaperone activity of sHsps against amorphously aggregating proteins has been well studied, its action against fibril-forming proteins has received less attention despite the presence of sHsps in deposits found in fibril-associated diseases (e.g. Alzheimer's and Parkinson's). In this review, the literature on the interaction of αB-crystallin and other sHsps with fibril-forming proteins is summarized. In particular, the ability of sHsps to prevent fibril formation, their mechanisms of action and the possible in vivo consequences of such associations are discussed. Finally, the fibril-forming propensity of the crystallin proteins and its implications for cataract formation are described along with the potential use of fibrillar crystallin proteins as bionanomaterials.

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“…However, mechanistic details seem to depend on the stability of the protein aggregates that are formed with the aid of EGCG. Carboxymethylated casein forms fibrils with β-sheet structure that bind to the amyloid dye thioflavin T; it has, therefore, been used as a generic model system for amyloid formation [97]. EGCG inhibits the fibril formation of casein through its binding to a β-sheet-turnsheet motif of the protein [98].…”

Section: Mechanism Of Egcg Interventionmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Dissociation from the Oligomeric State Is the Rate-limiting Step in Fibril Formation by κ-Casein

Cited by 79 publications

References 46 publications

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Crystallin proteins and amyloid fibrils

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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