The dissociated form of κ-casein is the precursor to its amyloid fibril formation

Ecroyd, Heath; Thorn, David C.; Li, Yanqin; Carver, John A.

doi:10.1042/bj20091949

Cited by 51 publications

(64 citation statements)

References 41 publications

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“…In addition, dissociation of partially unfolded monomeric states from an oligomeric state can be rate-limiting for protein aggregation 45–47 . A key example is the homotetrameric protein transthyretin, where tetramer dissociation and partial unfolding of the monomer preceeds amyloid formation 46,47 .…”

Section: Discussionmentioning

confidence: 99%

Cold denaturation of a protein dimer monitored at atomic resolution

Jaremko

Kim

et al. 2013

Nat Chem Biol

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Protein folding and unfolding are crucial for a range of biological phenomena and human diseases. Defining the pathways of protein folding and unfolding is crucial for understanding the origins of a range of biological phenomena and human diseases. However, little is known about the involved structural changes because the species populated during folding and unfolding are highly transient and therefore difficult to grasp by current technology. We have overcome these limitations by a combination of nuclear magnetic resonance spectroscopy with cold-induced unfolding of a homodimeric protein in supercooled solution. Seven three-dimensional structures of the Enterococcus faecalis repressor protein CylR2 at temperatures from 25 °C to −16 °C reveal a progressive dissociation of the dimer into a native-like monomeric intermediate followed by transition into a highly dynamic, partially folded state. The core of the partially folded state appears critical for biological function and misfolding.

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Section: Discussionmentioning

confidence: 99%

Cold denaturation of a protein dimer monitored at atomic resolution

Jaremko

Kim

et al. 2013

Nat Chem Biol

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“…Neither β-nor α S1 -casein has been observed to form amyloid fibrils under physiological conditions. We and others have proposed that the bovine κ-casein fibril core is located somewhere between Tyr25 and Lys86 ( Ecroyd, et al 2008;Ecroyd, Thorn, Liu, & Carver, 2010;Farrell, Cooke, Wickham, Piotrowski, & Hoagland, 2003) because, upon fibril formation, this region is resistant to proteolysis. Presumably this is because of the incorporation into, and thus burial of, at least part of this region in the β-sheet fibril core.…”

Section: Caseins Can Form Amyloid Fibrilsmentioning

confidence: 99%

Casein structures in the context of unfolded proteins

Thorn

Ecroyd

Carver

et al. 2015

International Dairy Journal

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Caseins were among the first proteins to be recognised as functional but unfolded. Many others are now known, providing better models of casein behaviour than either detergents or folded proteins. Caseins are members of a paralogous group of unfolded phosphoproteins, some of which share the ability to sequester amorphous calcium phosphate through phosphate centres. Non-covalent interactions of caseins can be through Pro-and Gln-rich sequences. Similar sequences in other unfolded proteins can also form open and highly hydrated structures such as gels, mucus and slimes. Many unfolded proteins, including κ-and αS2-caseins, can form amyloid fibrils under physiological conditions. The sequence-specific interactions that lead to fibrils can be reduced or eliminated by low specificity interactions among a mixture of caseins to yield, instead, amorphous aggregates. The size of amorphous whole casein aggregates is limited by the C-terminal half of κ-casein whose sequence resembles that of a soluble mucin. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences

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“…We and others have proposed that the bovine κ-CN fibril core is encompassed by the Tyr 25 -Lys 86 region (Farrell et al, 2003;Ecroyd et al, , 2010 because, upon fibril formation, this region is protected from limited proteolysis by the incorporation into, and thus burial of, at least part of this region in the β-sheet fibril core . Examination of the AA sequence strongly supports this proposal: Tyr 25 -Lys 86 is in the adhesive part of a P,Q-rich sequence derived from exon 4 (Supplementary Table S4; http://dx.doi.…”

Section: Casein Amyloid Fibrilsmentioning

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

385

240

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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...

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The dissociated form of κ-casein is the precursor to its amyloid fibril formation

Cited by 51 publications

References 41 publications

Cold denaturation of a protein dimer monitored at atomic resolution

Cold denaturation of a protein dimer monitored at atomic resolution

Casein structures in the context of unfolded proteins

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

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