Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders

Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.

doi:10.1101/cshperspect.a010454

Cited by 88 publications

(72 citation statements)

References 63 publications

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“…Such a structure is of great interest, because the thermodynamic and kinetic properties of amyloid fibrils, as well as their frequently adverse effects on cellular homeostasis leading to disease, are linked to the details of their morphological features (40). In this study, we have resolved each of the structural elements in a cross-β amyloid fibril to atomic resolution, thus revealing the structural basis for the hierarchical organization of these aggregates.…”

Section: Discussionmentioning

confidence: 99%

Atomic structure and hierarchical assembly of a cross-β amyloid fibril

Fitzpatrick

Debelouchina

Bayro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

503

518

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The cross-β amyloid form of peptides and proteins represents an archetypal and widely accessible structure consisting of ordered arrays of β-sheet filaments. These complex aggregates have remarkable chemical and physical properties, and the conversion of normally soluble functional forms of proteins into amyloid structures is linked to many debilitating human diseases, including several common forms of age-related dementia. Despite their importance, however, cross-β amyloid fibrils have proved to be recalcitrant to detailed structural analysis. By combining structural constraints from a series of experimental techniques spanning five orders of magnitude in length scale-including magic angle spinning nuclear magnetic resonance spectroscopy, X-ray fiber diffraction, cryoelectron microscopy, scanning transmission electron microscopy, and atomic force microscopy-we report the atomic-resolution (0.5 Å) structures of three amyloid polymorphs formed by an 11-residue peptide. These structures reveal the details of the packing interactions by which the constituent β-strands are assembled hierarchically into protofilaments, filaments, and mature fibrils. It is well established that a wide variety of peptides or proteins without any evident sequence similarity can self-assemble into amyloid fibrils (1, 2). These structures have many common characteristics, typically being 100-200 Å in diameter and containing a universal "cross-β" core structure composed of arrays of β-sheets running parallel to the long axis of the fibrils (3). These fibrillar states are highly ordered, with persistence lengths of the order of microns (4) and mechanical properties comparable to those of steel and dragline silk, and much greater than those typical of biological filaments such as actin and microtubules (5). Amyloid fibrils can also possess very high kinetic and thermodynamic stabilities, often exceeding those of the functional folded states of proteins (6), as well as a greater resistance to degradation by chemical or biological means (7). Several functional forms of proteins that exploit these properties have been observed in biological systems (8). More generally, however, the conversion of normally soluble functional proteins into the amyloid state is associated with many debilitating human disorders, ranging from Alzheimer's disease to type II diabetes (1, 9). Our understanding of the nature of this type of filamentous aggregate has greatly improved in recent years (3,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), particularly through the structural determination of their elementary β-strand building blocks (20) and the characterization of their assembly into cross-β steric zippers (21,22). However, a thorough understanding of the hierarchical assembly of these individual structural elements into fully-formed fibrils, which display polymorphism but possess a range of generic features (23), has so far been limited by the absence of a complete atomicresolution cross-β amyloid structures (2).We report here the simultaneous determination of the a...

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Section: Discussionmentioning

confidence: 99%

Atomic structure and hierarchical assembly of a cross-β amyloid fibril

Fitzpatrick

Debelouchina

Bayro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

503

518

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“…A fine balance exists between keeping a protein in solution at a sufficiently high concentration to meet biological requirements and its precipitation, resulting in the possible formation of an insoluble and inactive deposit (Baldwin and Zimm, 2000;Vendruscolo et al, 2011). The production of deposits in the form of plaques and inclusion bodies has been associated with a variety of so-called protein conformational or protein misfolding diseases (e.g., Alzheimer's disease, Parkinson's disease, type-II diabetes, and cataracts).…”

Section: Prevention Of Protein Aggregation By Molecular Chaperonesmentioning

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

393

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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“…Amyloid formation is known to cause other diseases characterized by similar misfolding processes. In each of these diseases, a major protein forms intra-or extracellular aggregates, leading to cellular dysfunction 35 ; in particular, Aβ and Tau protein are involved in Alzheimer disease (AD), α-synuclein is involved in Parkinson disease (PD), huntingtin is involved in Huntington disease and superoxide dismutase (SOD) and TDP-43 are involved in amyothropic lateral sclerosis (ALS).…”

Section: Prion-like Mechanisms and Prionoid Proteinsmentioning

confidence: 99%