Aβ(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease

Xiao, Yiling; Ma, Buyong; McElheny, Dan; Parthasarathy, Sudhakar; Long, Fei; Hoshi, Minako; Nussinov, Ruth; Ishii, Yoshitaka

doi:10.1038/nsmb.2991

Cited by 731 publications

(944 citation statements)

References 58 publications

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“…Notably, the triple mutation F19S, F20S, I31P entirely abolished [PSI + ] nucleation by both Sup35N-Aβ1-42 ( Fig 5D, Table 1) and Sup35NM-Aβ1-42 ( Table 1). The K to E substitution, affecting the β3 strand and disrupting a presumable "salt bridge" that involves position K28 (e. g. [44,50], also significantly decreased [PSI + ] nucleation by Sup35N-Aβ1-42 in yeast (Fig 5E). In contrast, the substitution D23N, a so-called "Iowa mutation" associated with the heritable form of AD [11,13], significantly increased [PSI + ] nucleation in yeast ( Fig 5F).…”

Section: Mammalianmentioning

confidence: 98%

Mammalian amyloidogenic proteins promote prion nucleation in yeast

Chandramowlishwaran

Sun

Casey

et al. 2018

Journal of Biological Chemistry

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Fibrous cross-β aggregates (amyloids) and their transmissible forms (prions) cause diseases in mammals (including humans) and control heritable traits in yeast. Initial nucleation of a yeast prion by transiently overproduced prion-forming protein or its (typically, QN-rich) prion domain is efficient only in the presence of another aggregated (in most cases, QN-rich) protein. Here, we demonstrate that a fusion of the prion domain of yeast protein Sup35 to some non-QN-rich mammalian proteins, associated with amyloid diseases, promotes nucleation of Sup35 prions in the absence of preexisting aggregates. In contrast, both a fusion of the Sup35 prion domain to a multimeric nonamyloidogenic protein, and an expression of a mammalian amyloidogenic protein that is not fused to the Sup35 prion domain failed to promote prion nucleation, further indicating that physical linkage of a mammalian amyloidogenic protein to the prion domain of a yeast protein is required for the nucleation of a yeast prion. Biochemical and cytological approaches confirmed the nucleation of protein aggregates in the yeast cell. Sequence alterations antagonizing or enhancing amyloidogenicity of human β amyloid (Aβ, associated with Alzheimer disease) and mouse PrP (associated with prion diseases) respectively antagonized or enhanced nucleation of a yeast prion by these proteins. The yeast-based prion nucleation assay, developed in our work, can be employed for mutational dissection of amyloidogenic proteins. We anticipate that it will aid in the identification of chemicals that influence initial amyloid nucleation and in searching for new amyloidogenic proteins in a variety of proteomes.

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Section: Mammalianmentioning

confidence: 98%

Mammalian amyloidogenic proteins promote prion nucleation in yeast

Chandramowlishwaran

Sun

Casey

et al. 2018

Journal of Biological Chemistry

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“…This self-quenching mechanism is responsible for the observed time-dependent decrease in fluorescence emission of the HiLyte Fluor 555 dye [34] as the aggregation progresses and depends on the proximity and local density of identical dyes in the neighborhood of a given fluorophore (Figure 2). An in-register parallel beta-sheet packing placing the N-terminal domains next to each other, has been recently reported using solid-state NMR, [43] thus providing a molecular-level explanation of how the organization of the amyloid fibrils enables a very efficient self-quenching process. As suggested in that work, hydrophobic assembly of two or more of these protofibrils might be possible and this could additionally contribute to place the dyes in close proximity.…”

Section: Monitoring Amyloid Aggregation and Inhibition Using Fluorescmentioning

confidence: 99%

“…As suggested in that work, hydrophobic assembly of two or more of these protofibrils might be possible and this could additionally contribute to place the dyes in close proximity. [43] 17-HSD10 inhibits the formation of fibril-like structures…”

Section: Monitoring Amyloid Aggregation and Inhibition Using Fluorescmentioning

confidence: 99%

“…[43] Secondly, aggregation protocols to reproducibly promote the formation of these A aggregates are well-established and the resulting aggregates have been extensively characterized using structural imaging methods including atomic-force microscopy (AFM) and electron-microscopy (EM). [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] In a previous study we have already shown using EM that the presence of the HiLyte Fluor 555 dye at the N-terminus of the A(1-42) peptide (A 555 ) does not affect the aggregation kinetics or the morphology of the aggregates. [34] Indeed, we observed amyloid structures of A 555 with diameters of ~ 4 nm (fibrils) and ~ 22 nm (globules) which are identical to those obtained in the absence of N-terminal functionalization.…”

Section: Monitoring Amyloid Aggregation and Inhibition Using Fluorescmentioning

confidence: 99%

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Morphology‐Specific Inhibition of β‐Amyloid Aggregates by 17β‐Hydroxysteroid Dehydrogenase Type 10

et al. 2016

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A major hallmark of Alzheimer's disease (AD) is the formation of toxic aggregates composed of the -amyloid peptide (A). Given that A peptides are known to co-localize within mitochondria and interact with 17-HSD10, a mitochondrial protein expressed at high levels in AD brains, we have investigated the inhibitory potential of 17-HSD10 against A aggregation across a range of physiological conditions. The fluorescence self-quenching (FSQ) of A(1-42), labelled with HiLyte Fluor 555, was used as a sensing strategy to evaluate the inhibitory effect of 17-HSD10 under wellestablished conditions to grow distinct A morphologies. Our results indicate that 17-HSD10 preferentially inhibits the formation of globular and fibrillar-like structures but has no effect on the growth of amorphous plaque-like aggregates at endosomal pH 6. This work provides insights into the dependence of the A-17-HSD10 interaction with the morphology of A aggregates and how this impacts enzymatic function.Keywords: -Amyloid peptide; 17-hydroxysteroid dehydrogenase type 10; Alzheimer's disease; fluorescence self-quenching; neurochemistry

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“…[43][44][45] In the same way, several Aβ structures have recently resoluted by ssNMR. 46,47 These compelling evidences suggest that macroscopic polymorphism could also be a potential cause of the usual low resolution of the Aβ ssNMR spectra.…”

mentioning

confidence: 99%

Amyloids in solid-state nuclear magnetic resonance: potential causes of the usually low resolution

Espargaró¹,

Busquets²,

Estelrich³

et al. 2015

IJN

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Amyloids are non-crystalline and insoluble, which imply that the classical structural biology tools, ie, X-ray crystallography and solution nuclear magnetic resonance (NMR), are not suitable for their analysis. In the last years, solid-state NMR (ssNMR) has emerged as an alternative tool to decrypt the structural signatures of amyloid fibrils, providing major contributions to our understanding of molecular structures of amyloids such as β-amyloid peptide associated with Alzheimer's disease or fungal prions, among others. Despite this, the wide majority of amyloid fibrils display low resolution by ssNMR. Usually, this low resolution has been attributed to a high disorder or polymorphism of the fibrils, suggesting the existence of diverse elementary β-sheet structures. Here, we propose that a single β-sheet structure could be responsible for the broadening of the line widths in the ssNMR spectra. Although the fibrils and fibers consist of a single elementary structure, the angle of twist of each individual fibril in the mature fiber depends on the number of individual fibrils as well as the fibril arrangement in the final mature fiber. Thus, a wide range of angles of twist could be observed in the same amyloid sample. These twist variations involve changes in amino acid alignments that could be enough to limit the ssNMR resolution.

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Aβ(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease

Cited by 731 publications

References 58 publications

Mammalian amyloidogenic proteins promote prion nucleation in yeast

Mammalian amyloidogenic proteins promote prion nucleation in yeast

Morphology‐Specific Inhibition of β‐Amyloid Aggregates by 17β‐Hydroxysteroid Dehydrogenase Type 10

Amyloids in solid-state nuclear magnetic resonance: potential causes of the usually low resolution

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