The Structural Biology of Protein Aggregation Diseases:  Fundamental Questions and Some Answers

Eisenberg, David; Nelson, Rebecca A.; Sawaya, M.R.; Balbirnie, Melinda; Sambashivan, Shilpa; Ivanova, Magdalena I.; Madsen, Anders Ø.; Riekel, Christian

doi:10.1021/ar0500618

Cited by 173 publications

(128 citation statements)

References 68 publications

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“…Several studies have indicated that polyglutamine aggregates are connected with neurodegeneration or cytotoxicity (6,7,10,11), whereas other studies have suggested that aggregate formation is either not intimately correlated with cytotoxicity (12)(13)(14)(15) or plays a protective role in cells (16). This apparent inconsistency may be caused by structural diversity of amyloid, as amyloid-forming proteins often misfold into more than 1 conformation and the phenotypic and pathologic consequence of harboring aggregates depends critically on the specific amyloid form a protein adopts (17)(18)(19)(20)(21). A striking example of this observation is the prion strain phenomenon.…”

mentioning

confidence: 99%

Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity

Nekooki-Machida¹,

Kurosawa

Nukina

et al. 2009

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

208

224

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A hallmark of polyglutamine diseases, including Huntington disease (HD), is the formation of ␤-sheet-rich aggregates, called amyloid, of causative proteins with expanded polyglutamines. However, it has remained unclear whether the polyglutamine amyloid is a direct cause or simply a secondary manifestation of the pathology. Here we show that huntingtin-exon1 (thtt) with expanded polyglutamines remarkably misfolds into distinct amyloid conformations under different temperatures, such as 4°C and 37°C. The 4°C amyloid has loop/turn structures together with mostly ␤-sheets, including exposed polyglutamines, whereas the 37°C amyloid has more extended and buried ␤-sheets. By developing a method to efficiently introduce amyloid into mammalian cells, we found that the formation of the 4°C amyloid led to substantial toxicity, whereas the toxic effects of the 37°C amyloid were very small. Importantly, thtt amyloids in different brain regions of HD mice also had distinct conformations. The thermolabile thtt amyloid with loop/turn structures in the striatum showed higher toxicity, whereas the rigid thtt amyloid with more extended ␤-sheets in the hippocampus and cerebellum had only mild toxic effects. These studies show that the thtt protein with expanded polyglutamines can misfold into distinct amyloid conformations and, depending on the conformations, the amyloids can be either toxic or nontoxic. Thus, the amyloid conformation of thtt may be a critical determinant of cytotoxicity in HD.Huntington disease ͉ polyglutamine misfolding ͉ aggregation

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mentioning

confidence: 99%

Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity

Nekooki-Machida¹,

Kurosawa

Nukina

et al. 2009

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

208

224

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“…Amyloid fibril formation is characteristic of a variety of human disorders, including Huntington and Alzheimer diseases (1,2). In amyloid-related diseases, one or more proteins are found in fibrillar aggregates, in a non-native, highly ␤-sheetrich conformation.…”

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confidence: 99%

“…Many proteins can also be made to form amyloid fibrils in vitro. Intriguingly, there are many accounts of proteins that form amyloid-like fibrils that are not associated with pathologies (2). Whether disease-related or not, amyloid fibrils share key biochemical and biophysical characteristics, suggesting common structural features.…”

mentioning

confidence: 99%

Amyloid-like Fibrils from a Domain-swapping Protein Feature a Parallel, in-Register Conformation without Native-like Interactions

Hoop

Kodali

et al. 2011

Journal of Biological Chemistry

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The formation of amyloid-like fibrils is characteristic of various diseases, but the underlying mechanism and the factors that determine whether, when, and how proteins form amyloid, remain uncertain. Certain mechanisms have been proposed based on the three-dimensional or runaway domain swapping, inspired by the fact that some proteins show an apparent correlation between the ability to form domain-swapped dimers and a tendency to form fibrillar aggregates. Intramolecular ␤-sheet contacts present in the monomeric state could constitute intermolecular ␤-sheets in the dimeric and fibrillar states. One example is an amyloid-forming mutant of the immunoglobulin binding domain B1 of streptococcal protein G, which in its native conformation consists of a four-stranded ␤-sheet and one ␣-helix. Under native conditions this mutant adopts a domainswapped dimer, and it also forms amyloid-like fibrils, seemingly in correlation to its domain-swapping ability. We employ magic angle spinning solid-state NMR and other methods to examine key structural features of these fibrils. Our results reveal a highly rigid fibril structure that lacks mobile domains and indicate a parallel in-register ␤-sheet structure and a general loss of native conformation within the mature fibrils. This observation contrasts with predictions that native structure, and in particular intermolecular ␤-strand interactions seen in the dimeric state, may be preserved in "domain-swapping" fibrils. We discuss these observations in light of recent work on related amyloidforming proteins that have been argued to follow similar mechanisms and how this may have implications for the role of domain-swapping propensities for amyloid formation.Amyloid fibril formation is characteristic of a variety of human disorders, including Huntington and Alzheimer diseases (1, 2). In amyloid-related diseases, one or more proteins are found in fibrillar aggregates, in a non-native, highly ␤-sheetrich conformation. Depending on the disease context, the propensity for amyloid formation may be traced to mutations and cleavage events, combined with poorly understood external triggers. Many proteins can also be made to form amyloid fibrils in vitro. Intriguingly, there are many accounts of proteins that form amyloid-like fibrils that are not associated with pathologies (2). Whether disease-related or not, amyloid fibrils share key biochemical and biophysical characteristics, suggesting common structural features. Understanding the fibril formation pathway is of interest not only as there may be a correlation between disease onset and protein aggregation, but also because transient oligomeric precursors may act as toxic species. However, a lack of high resolution structures of most fibrils and their precursors limits our knowledge of the mechanism of formation.One seemingly common structural motif for amyloid fibrils is an in-register parallel (IP) 3 assembly into pleated ␤-sheets, stabilized by backbone-to-backbone hydrogen bonding, combined with favorable side-chain interactions (e....

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“…Folded proteins may aggregate by domain-swapping or by interaction with their surfaces, such as the so-called "end-to-end" stacking (Bennett et al 2006;Eisenberg et al 2006;Nelson and Eisenberg 2006a,b). Because such aggregates are based on interactions between folded proteins, there is not a gross rearrangement of the protein fold, and the repetitive nature of the structure is at the suprananomolar level, contrasting the subnanomolar repetitive nature of the amyloid, which gives rise to the many potential activities of the amyloid through cooperativity effects (see above).…”

Section: The Amyloid Compared To Other Protein Aggregatesmentioning

confidence: 99%

“…It is the aim of this review to discuss the structural nature of the cross-bsheet motif in detail and put its potential actions into perspective. Eisenberg et al (2006) determined the threedimensional (3D) structures of short fibrilforming peptide segments of amyloid proteins (such as PrP, Sup35, insulin, Ab, tau, and amylin) from microcrystals by X-ray crystallography (Nelson et al 2005;Nelson and Eisenberg 2006a,b;Sawaya et al 2007). The soluble peptides are able to form microcrystals as well as amyloid fibrils.…”

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confidence: 99%

The Three-Dimensional Structures of Amyloids

Riek

2016

Cold Spring Harb Perspect Biol

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Amyloids are highly ordered protein aggregates that are associated with both disease (including PrP prion, Alzheimer's, and Parkinson's) and biological function. The amyloid structure is composed of the cross-b-sheet entity, which is an almost indefinitely repeating twolayered intermolecular b-sheet motif. The three-dimensional (3D) structure is unique among protein folds because it folds only upon intermolecular contacts (for a folding to occur, only short sequences of amino acid residues are required), and the structure repeats itself at the atomic level (i.e., every 4.7 Å ). As a consequence of this structure, among others, it can grow by recruiting corresponding amyloid peptide/protein and thus has the capacity to be an infectious protein (i.e., a prion). Furthermore, its repetitiveness can translate what would be a nonspecific activity as monomer into a potent one through cooperativity. Because of these and other properties, the activities of amyloids are manifold and include peptide storage, template assistance, loss of function, gain of function, generation of toxicity, membrane binding, infectivity, and more. This review summarizes the structural nature of the cross-bsheet motif on the basis of a few high-resolution structural studies of amyloids in the context of potential biological activities.

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The Structural Biology of Protein Aggregation Diseases: Fundamental Questions and Some Answers

Cited by 173 publications

References 68 publications

Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity

Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity

Amyloid-like Fibrils from a Domain-swapping Protein Feature a Parallel, in-Register Conformation without Native-like Interactions

The Three-Dimensional Structures of Amyloids

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