The molecular lifecycle of amyloid – Mechanism of assembly, mesoscopic organisation, polymorphism, suprastructures, and biological consequences

Lutter, Liisa; Serpell, Christopher J.; Tuite, Mick F.; Xue, Wei‐Feng

doi:10.1016/j.bbapap.2019.07.010

Cited by 40 publications

(42 citation statements)

References 171 publications

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“…They can be self-assembled from a wide range of different proteins and peptides. Fibrils formed from some amyloidogenic sequences, including amyloid-b and tau, have been identified to be involved in human neurodegenerative pathologies, such as Alzheimer’s disease, whereas other amyloid forming sequences are known to be non-toxic and even required for normal physiological processes [14]. Although the amino acid sequences of the many amyloid forming proteins are typically unrelated, the fibrils they form share a well-defined common core structural architecture, namely the cross-β arrangement made up of β-strands that stack perpendicular to the fibril axis stabilised by intermolecular hydrogen bonds between β-strands that runs parallel to the fibril axis [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Despite that all amyloid fibrils share these core structural features, variations in filament packing arrangements, including fibrils assembled from the same precursors, result in a multitude of different fibril structures called polymorphs, which may be related to the varying types of biological response they elicit. Furthermore, specific structural polymorphs assembled from the same amyloid forming protein could be patient- or disease-specific and may correlate with neurodegenerative disease aetiology [14]. Due to the unresolved nature of the amyloid assembly structure-function relationship, fibrillar amyloid specimen are widely studied using AFM imaging to resolve the mechanistic roles of amyloid assembly and polymorphism [17].…”

Section: Introductionmentioning

confidence: 99%

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Three-dimensional reconstruction of individual helical nano-filament structures from atomic force microscopy topographs

Lutter

Serpell²,

Tuite

et al. 2020

Preprint

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ABSTRACTAtomic force microscopy, AFM, is a powerful tool that can produce detailed topographical images of individual nano-structures with a high signal-to-noise ratio without the need for ensemble averaging. However, the application of AFM in structural biology has been hampered by the tip-sample convolution effect, which distorts images of nano-structures, particularly those that are of similar dimensions to the cantilever probe tips used in AFM. Here we show that the tip-sample convolution results in a feature-dependent and non-uniform distribution of image resolution on AFM topographs. We show how this effect can be utilised in structural studies of nano-sized upward convex objects such as spherical or filamentous molecular assemblies deposited on a flat surface, because it causes ‘magnification’ of such objects in AFM topographs. Subsequently, this enhancement effect is harnessed through contact-point based deconvolution of AFM topographs. Here, the application of this approach is demonstrated through the 3D reconstruction of the surface envelope of individual helical amyloid filaments without the need of cross-particle averaging using the contact-deconvoluted AFM topographs. Resolving the structural variations of individual macromolecular assemblies within inherently heterogeneous populations is paramount for mechanistic understanding of many biological phenomena such as amyloid toxicity and prion strains. The approach presented here will also facilitate the use of AFM for high-resolution structural studies and integrative structural biology analysis of single molecular assemblies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Three-dimensional reconstruction of individual helical nano-filament structures from atomic force microscopy topographs

Lutter

Serpell²,

Tuite

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…(4) According to the fluorescence microscopy data, the fourth stage of amyloid formation by ABB can be differentiated, which involves the formation of large fibril bundles observed at long incubation times. The formation of the suprafibrillar structure is attributed to the fact that the backbone of an amyloid fibril typically contains only a small portion of the protein (~8-10 AAR) [1], while the remaining portion is somehow involved in the interaction between fibrils or in the formation of large bundles by them.…”

Section: Discussionmentioning

confidence: 99%

“…Protein misfolding and aggregation, when monomeric protein molecules turn into amyloid fibrils, is one of the factors causing severe disorders, including neurodegenerative diseases [1]. Amyloids are fibrils, usually unbranched, consisting of protein monomers linked by hydrogen bonds between β-strands of an intermolecular β-sheet; they lie perpendicularly to the axis of the fibril.…”

Section: Introductionmentioning

confidence: 99%

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The Kinetics of Amyloid Fibril Formation by de Novo Protein Albebetin and Its Mutant Variants

et al. 2020

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Engineering of amyloid structures is one of the new perspective areas of protein engineering. Studying the process of amyloid formation can help find ways to manage it in the interests of medicine and biotechnology. One of the promising candidates for the structural basis of artificial functional amyloid fibrils is albebetin (ABB), an artificial protein engineered under the leadership of O.B. Ptitsyn. Various aspects of the amyloid formation of this protein and some methods for controlling this process are investigated in this paper. Four stages of amyloid fibrils formation by this protein from the first non-fibrillar aggregates to mature fibrils and large micron-sized complexes have been described in detail. Dependence of albebetin amyloids formation on external conditions and some mutations also have been described. The introduction of similar point mutations in the two structurally identical α-β-β motifs of ABB lead to different amiloidogenesis kinetics. The inhibitory effect of a disulfide bond and high pH on amyloid fibrils formation, that can be used to control this process, was shown. The results of this work are a good basis for the further design and use of ABB-based amyloid constructs.

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Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer’s Pathogenesis

Almeida,

Vaz,

Brito

2024

Mol Neurobiol

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Alzheimer’s disease (AD) is the most common form of dementia around the world (~ 65%). Here, we portray the neuropathology of AD, biomarkers, and classification of amyloid plaques (diffuse, non-cored, dense core, compact). Tau pathology and its involvement with Aβ plaques and cell death are discussed. Amyloid cascade hypotheses, aggregation mechanisms, and molecular species formed in vitro and in vivo (on- and off-pathways) are described. Aβ42/Aβ40 monomers, dimers, trimers, Aβ‐derived diffusible ligands, globulomers, dodecamers, amylospheroids, amorphous aggregates, protofibrils, fibrils, and plaques are characterized (structure, size, morphology, solubility, toxicity, mechanistic steps). An update on AD-approved drugs by regulatory agencies, along with new Aβ-based therapies, is presented. Beyond prescribing Aβ plaque disruptors, cholinergic agonists, or NMDA receptor antagonists, other therapeutic strategies (RNAi, glutaminyl cyclase inhibitors, monoclonal antibodies, secretase modulators, Aβ aggregation inhibitors, and anti-amyloid vaccines) are already under clinical trials. New drug discovery approaches based on “designed multiple ligands”, “hybrid molecules”, or “multitarget-directed ligands” are also being put forward and may contribute to tackling this highly debilitating and fatal form of human dementia.

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The molecular lifecycle of amyloid – Mechanism of assembly, mesoscopic organisation, polymorphism, suprastructures, and biological consequences

Abstract: The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.

Cited by 40 publications

References 171 publications

Three-dimensional reconstruction of individual helical nano-filament structures from atomic force microscopy topographs

Three-dimensional reconstruction of individual helical nano-filament structures from atomic force microscopy topographs

The Kinetics of Amyloid Fibril Formation by de Novo Protein Albebetin and Its Mutant Variants

Morphological and Molecular Profiling of Amyloid-β Species in Alzheimer’s Pathogenesis

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