αB-Crystallin inhibits the cell toxicity associated with amyloid fibril formation by κ-casein and the amyloid-β peptide

Dehle, Francis C.; Ecroyd, Heath; Musgrave, Ian; Carver, John A.

doi:10.1007/s12192-010-0212-z

Cited by 63 publications

(65 citation statements)

References 63 publications

(124 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, α S1 -and β-CN can also prevent the formation of fibrillar structures by target proteins, including α S2 -and κ-CN (Thorn et al, 2005, ovalbumin (Khodarahmi et al, 2008), and amyloid-β peptide (Carrotta et al, 2012). Fibril formation by κ-CN is cytotoxic to PC-12 cells grown in culture but the effects are inhibited by α S -or β-CN (Dehle et al, 2010). More recently, it has been shown that α S2 -CN is also toxic to PC-12 cells and the neuronal cell line SH-SY5Y [Kegomoditswe Regoeng (University of Adelaide, Australia), John A.…”

Section: The Chaperone Action Of Caseinsmentioning

confidence: 99%

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

Holt

Carver

Ecroyd

et al. 2013

Journal of Dairy Science

392

240

View full text Add to dashboard Cite

A typical casein micelle contains thousands of casein molecules, most of which form thermodynamically stable complexes with nanoclusters of amorphous calcium phosphate. Like many other unfolded proteins, caseins have an actual or potential tendency to assemble into toxic amyloid fibrils, particularly at the high concentrations found in milk. Fibrils do not form in milk because an alternative aggregation pathway is followed that results in formation of the casein micelle. As a result of forming micelles, nutritious milk can be secreted and stored without causing either pathological calcification or amyloidosis of the mother's mammary tissue. The ability to sequester nanoclusters of amorphous calcium phosphate in a stable complex is not unique to caseins. It has been demonstrated using a number of noncasein secreted phosphoproteins and may be of general physiological importance in preventing calcification of other biofluids and soft tissues. Thus, competent noncasein phosphoproteins have similar patterns of phosphorylation and the same type of flexible, unfolded conformation as caseins. The ability to suppress amyloid fibril formation by forming an alternative amorphous aggregate is also not unique to caseins and underlies the action of molecular chaperones such as the small heat-shock proteins. The open structure of the protein matrix of casein micelles is fragile and easily perturbed by changes in its environment. Perturbations can cause the polypeptide chains to segregate into regions of greater and lesser density. As a result, the reliable determination of the native structure of casein micelles continues to be extremely challenging. The biological functions of caseins, such as their chaperone activity, are determined by their composition and flexible conformation and by how the casein polypeptide chains interact with each other. These same properties determine how caseins behave in the manufacture of many dairy products and how they can be used as functional ingredients in other foods. aBStraCtA typical casein micelle contains thousands of casein molecules, most of which form thermodynamically stable complexes with nanoclusters of amorphous calcium phosphate. Like many other unfolded proteins, caseins have an actual or potential tendency to assemble into toxic amyloid fibrils, particularly at the high concentrations found in milk. Fibrils do not form in milk because an alternative aggregation pathway is followed that results in formation of the casein micelle. As a result of forming micelles, nutritious milk can be secreted and stored without causing either pathological calcification or amyloidosis of the mother's mammary tissue. The ability to sequester nanoclusters of amorphous calcium phosphate in a stable complex is not unique to caseins. It has been demonstrated using a number of noncasein secreted phosphoproteins and may be of general physiological importance in preventing calcification of other biofluids and soft tissues. Thus, competent noncasein phosphoproteins have similar patterns of phosp...

show abstract

Section: The Chaperone Action Of Caseinsmentioning

confidence: 99%

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

Holt

Carver

Ecroyd

et al. 2013

Journal of Dairy Science

392

240

View full text Add to dashboard Cite

show abstract

“…The level of Bc expression in brains of patients suffering AD is markedly increased compared to that in the normal human brain [105,186] presumably due to the cellular stress caused by disease. We and others have shown that aggregation of A and its associated cellular toxicity is prevented by Bc [187] or its isolated ACD [18] and thus sHsp overexpression in the context of AD may be as a protective mechanism. Fändrich et al have shown that there is an intracellular component to the aggregation and pathogenic nature of A which may explain the presence of Bc in the extracellular plaques of AD [188].…”

Section: The Role Of Shsps In Neurodegenerative Diseasementioning

confidence: 99%

Small heat-shock proteins: important players in regulating cellular proteostasis

Treweek

Meehan

Ecroyd

et al. 2014

Cell. Mol. Life Sci.

Self Cite

180

177

View full text Add to dashboard Cite

Small heat-shock proteins (sHsps) are a diverse family of intra-cellular molecular chaperone proteins that play a critical role in mitigating and preventing protein aggregation under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) thereby avoiding the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. Significant progress has been made of late in understanding the structure and chaperone mechanism of sHsps. In this review, we discuss some of these advances, with a focus on mammalian sHsp hetero-oligomerisation, the mechanism by which sHsps act as molecular chaperones to prevent both amorphous and fibrillar protein aggregation, and the role of posttranslational modifications in sHsp chaperone function, particularly in the context of disease. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abstract (word count = 159)Small heat-shock proteins (sHsps) are a diverse family of intracellular molecular chaperone proteins that play a critical role in preventing protein unfolding, misfolding and aggregation, particularly under stress conditions such as elevated temperature, oxidation and infection. In doing so, they assist in the maintenance of protein homeostasis (proteostasis) and thereby avoid the deleterious effects that result from loss of protein function and/or protein aggregation. The chaperone properties of sHsps are therefore employed extensively in many tissues to prevent the development of diseases associated with protein aggregation. There has been much research into the structure and mechanism of chaperone action of sHsps over approximately the past 30 years, and significant progress has been made of late, however, there are still many unanswered questions relating to these aspects of sHsps. In this review, we outline some of the recent advances in understanding the structure and function of mammalian sHsps, particularly in the context of their many and varied roles in disease.

show abstract

“…Each treatment had six replicates. After a further 48 h of incubation, the treated cells were tested for viability by the MTT assay [29] using a BMG Polarstar microplate reader (BMG Labtechnologies, Germany). The results of the MTT assay were statistically analysed using one-way analysis of variance (ANOVA) followed by a Dunnett's comparison test (GraphPad PRISM V6).…”

Section: Methyl Tetrazolium Bromide Assaymentioning

confidence: 99%

Hemin as a generic and potent protein misfolding inhibitor

Carver

et al. 2014

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

After the embargo period via non-commercial hosting platforms such as their institutional repository  via commercial sites with which Elsevier has an agreement In all cases accepted manuscripts should: link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article AbstractProtein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer's disease, Parkinson's disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide, and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases. Highlights Hemin prevents Aβ42, α-synuclein, and RCM-κ-casein forming amyloid fibrils  Hemin inhibits the β-sheet structure formation of Aβ42  Hemin reduces the cell toxicity caused by fibrillar Aβ42  Hemin dissociates partially formed Aβ42 fibrils  Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin

show abstract

αB-Crystallin inhibits the cell toxicity associated with amyloid fibril formation by κ-casein and the amyloid-β peptide

Cited by 63 publications

References 63 publications

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

Invited review: Caseins and the casein micelle: Their biological functions, structures, and behavior in foods

Small heat-shock proteins: important players in regulating cellular proteostasis

Hemin as a generic and potent protein misfolding inhibitor

Contact Info

Product

Resources

About