Structure and Aggregation Mechanisms in Amyloids (original) (raw)
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Frontiers in Chemistry, 2022
Protein aggregation into highly ordered, regularly repeated cross-β sheet structures called amyloid fibrils is closely associated to human disorders such as neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases, or systemic diseases like type II diabetes. Yet, in some cases, such as the HET-s prion, amyloids have biological functions. High-resolution structures of amyloids fibrils from cryo-electron microscopy have very recently highlighted their ultrastructural organization and polymorphisms. However, the molecular mechanisms and the role of co-factors (posttranslational modifications, non-proteinaceous components and other proteins) acting on the fibril formation are still poorly understood. Whether amyloid fibrils play a toxic or protective role in the pathogenesis of neurodegenerative diseases remains to be elucidated. Furthermore, such aberrant protein-protein interactions challenge the search of small-molecule drugs or immunotherapy approaches targeting amyloid formation. In this review, we describe how chemical biology tools contribute to new insights on the mode of action of amyloidogenic proteins and peptides, defining their structural signature and aggregation pathways by capturing their molecular details and conformational heterogeneity. Challenging the imagination of scientists, this constantly expanding field provides crucial tools to unravel mechanistic detail of amyloid formation such as semisynthetic proteins and small-molecule sensors of conformational changes and/or aggregation. Protein engineering methods and bioorthogonal chemistry for the introduction of protein chemical modifications are additional fruitful strategies to tackle the challenge of understanding amyloid formation.
Faculty of 1000 evaluation for Fibril structure of amyloid-ß(1-42) by cryoelectron microscopy
F1000 - Post-publication peer review of the biomedical literature, 2017
Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer's disease patients. We present the structure of an Aβ(1-42) fibril composed of two intertwined protofilaments determined by cryo-electron microscopy (cryo-EM) to 4.0 Å resolution, complemented by solid-state nuclear magnetic resonance (NMR) experiments. The backbone of all 42 residues and nearly all sidechains are well resolved in the EM density map, including the entire N-terminus, which is part of the cross-β structure resulting in an overall "LS"-shaped topology of individual subunits. The dimer interface protects the hydrophobic C-termini from the solvent. The unique staggering of the non-planar subunits results in markedly different fibril ends, termed "groove" and "ridge", leading to different binding pathways on both fibril ends, which has implications for fibril growth.
Amyloid structure and assembly: Insights from scanning transmission electron microscopy
Journal of Structural Biology, 2011
Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).
Cryo-EM of amyloid fibrils and cellular aggregates
Current Opinion in Structural Biology
Neurodegenerative and other protein misfolding diseases are associated with the aggregation of a protein, which may be mutated in genetic forms of disease, or the wild type form in late onset sporadic disease. A wide variety of proteins and peptides can be involved, with aggregation originating from a natively folded or a natively unstructured species. Large deposits of amyloid fibrils are typically associated with cell death in late stage pathology. In this review, we illustrate the contributions of cryo-EM and related methods to the structure determination of amyloid fibrils extracted post mortem from patient brains or formed in vitro. We also discuss cell models of protein aggregation and the contributions of electron tomography to understanding the cellular context of aggregation.
Review: structure of amyloid fibril in diseases
Journal of Biomedical Science and Engineering, 2009
Tissue deposition of normally soluble proteins, or their fragments, as insoluble amyloid fibrils causes both acquired and hereditary systemic amyloidoses, which is usually fatal. Amyloid is associated with serious diseases such as Alzheimer's disease, type 2 diabetes, Parkinson's Disease, Huntington's Disease, cancer and the transmissible spongiform encephalopathies. Information concerning the structure and mechanism of formation of fibrils in these diseases is critical for understanding the process of pathology of the amyloidoses and to the development of more effective therapeutic agents that target the underlying disease mechanisms. Structural models have been made using information from a wide variety of techniques, including electron microscopy, X-ray diffraction, solid state NMR, and Congo red and CD spectroscopy. Although each type of amyloidosis is characterised by a specific amyloid fibril protein, the deposits share pathognomonic histochemical properties and the structural morphology of all amyloid fibrils is very similar. In fact, the structural similarity that defines amyloid fibres exists principally at the level of β-sheet folding of the polypeptides within the protofilament, while the different types vary in the supramolecular assembly of their protofilaments.
Biochimie, 2017
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. Formation of amyloid plaques consisting of amyloid-β peptides (Aβ) is one of the hallmarks of AD. Several lines of evidence have shown a correlation between the Aβ aggregation and the disease development. Extensive research has been conducted with the aim to reveal the structures of the neurotoxic Aβ aggregates. However, the exact structure of pathological aggregates and mechanism of the disease still remains elusive due to complexity of the occurring processes and instability of various disease relevant Aβ species. In this article we review up-to-date structural knowledge about amyloid-β peptides, focusing on data acquired using solution and solid state NMR techniques. Furthermore, we discuss implications from these structural studies on the mechanisms of aggregation and neurotoxicity.
Proceedings of the National Academy of Sciences, 2009
Recent experimental evidence points to intermediates populated during the process of amyloid fibril formation as the toxic moieties primarily responsible for the development of increasingly common disorders such as Alzheimer's disease and type II diabetes. We describe here the application of a pulse-labeling hydrogendeuterium (HD) exchange strategy monitored by mass spectrometry (MS) and NMR spectroscopy (NMR) to characterize the aggregation process of an SH3 domain under 2 different conditions, both of which ultimately lead to well-defined amyloid fibrils. Under one condition, the intermediates appear to be largely amorphous in nature, whereas under the other condition protofibrillar species are clearly evident. Under the conditions favoring amorphous-like intermediates, only species having no protection against HD exchange can be detected in addition to the mature fibrils that show a high degree of protection. By contrast, under the conditions favoring protofibrillar-like intermediates, MS reveals that multiple species are present with different degrees of HD exchange protection, indicating that aggregation occurs initially through relatively disordered species that subsequently evolve to form ordered aggregates that eventually lead to amyloid fibrils. Further analysis using NMR provides residue-specific information on the structural reorganizations that take place during aggregation, as well as on the time scales by which they occur.
Most neurodegenerative diseases have the characteristics of proteinopathies, i.e. they cause lesions to appear in vulnerable regions of the nervous system, corresponding to protein aggregates that progressively spread through the neuronal network as the symptoms progress. Alzheimer's disease is one of these proteinopathies. It is characterized by two lesions, neurofibrillary tangles (NFTs) and senile plaques, formed essentially of amyloid peptides (Aβ). A combination of factors ranging from genetic mutations to age-related changes in the cellular context converge in this disease to accelerate Aβ deposition. Over the last two decades, numerous studies have attempted to elucidate how structural determinants of its precursor (APP) modify Aβ production, and to understand the processes leading to the formation of different Aβ aggregates; e.g. fibrils and oligomers. The synthesis proposed in this review indicates that the same motifs can control APP function and Aβ production essentia...
Diverse Structural Conversion and Aggregation Pathways of Alzheimerʼs Amyloid-β (1–40)
ACS Nano, 2019
Complex amyloid aggregation of amyloid- (1-40) (A 1-40) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of A 1-40 aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of A 1-40 induced by low solvent polarity accelerated cytotoxic A 1-40 amyloid fibrillation while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of -structure-rich protofibrils or oligomers via aggregation-prone helical structures. Modulation of the pH and salt concentration transformed oligomers to protofibrils, which proceeded to amyloid formation. We reveal diverse molecular mechanisms underlying A 1-40 aggregation with conceptual energy diagrams and propose that aggregationprone partial helical structures are key to inducing amyloidogenesis. We demonstrate that contextdependent protein aggregation is comprehensively understood using the macroscopic phase diagram, which provides general insights into differentiation of amyloid formation and phase separation from unfolded and folded structures.