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Cell Sep 2021The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike... (Review)
Review
The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike globular proteins, amyloid proteins flatten and stack into unbranched fibrils. Stranger still, a single protein sequence can adopt wildly different two-dimensional conformations, yielding distinct fibril polymorphs. Thus, an amyloid protein may define distinct diseases depending on its conformation. At the heart of this conformational variability lies structural frustrations. In functional amyloids, evolution tunes frustration levels to achieve either stability or sensitivity according to the fibril's biological function, accounting for the vast versatility of the amyloid fibril scaffold.
Topics: Amyloidogenic Proteins; Animals; Disease; Evolution, Molecular; Humans; Polymorphism, Genetic; Protein Folding; Protein Stability
PubMed: 34534463
DOI: 10.1016/j.cell.2021.08.013 -
Journal of Cell Science Apr 2018Amyloid fibrils are protein homopolymers that adopt diverse cross-β conformations. Some amyloid fibrils are associated with the pathogenesis of devastating... (Review)
Review
Amyloid fibrils are protein homopolymers that adopt diverse cross-β conformations. Some amyloid fibrils are associated with the pathogenesis of devastating neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Conversely, functional amyloids play beneficial roles in melanosome biogenesis, long-term memory formation and release of peptide hormones. Here, we showcase advances in our understanding of amyloid assembly and structure, and how distinct amyloid strains formed by the same protein can cause distinct neurodegenerative diseases. We discuss how mutant steric zippers promote deleterious amyloidogenesis and aberrant liquid-to-gel phase transitions. We also highlight effective strategies to combat amyloidogenesis and related toxicity, including: (1) small-molecule drugs (e.g. tafamidis) to inhibit amyloid formation or (2) stimulate amyloid degradation by the proteasome and autophagy, and (3) protein disaggregases that disassemble toxic amyloid and soluble oligomers. We anticipate that these advances will inspire therapeutics for several fatal neurodegenerative diseases.
Topics: Amyloid; Humans
PubMed: 29654159
DOI: 10.1242/jcs.189928 -
Protein Science : a Publication of the... Sep 2019In this article, we consider the role of heterogeneous nucleation in β-amyloid aggregation. Heterogeneous nucleation is more common and occurs at lower levels of... (Review)
Review
In this article, we consider the role of heterogeneous nucleation in β-amyloid aggregation. Heterogeneous nucleation is more common and occurs at lower levels of supersaturation than homogeneous nucleation. The nucleation period is also the stage at which most of the polymorphism of amyloids arises, this being one of the defining features of amyloids. We focus on several well-known heterogeneous nucleators of β-amyloid, including lipid surfaces, especially those enriched in gangliosides and cholesterol, and divalent metal ions. These two broad classes of nucleators affect β-amyloid particularly in light of the amphiphilicity of these peptides: the N-terminal region, which is largely polar and charged, contains the metal binding site, whereas the C-terminal region is aliphatic and is important in lipid binding. Notably, these two classes of nucleators can interact cooperatively, aggregation begetting greater aggregation.
Topics: Amyloid beta-Peptides; Animals; Binding Sites; Humans; Membrane Lipids; Metals; Protein Aggregates; Protein Domains
PubMed: 31276610
DOI: 10.1002/pro.3674 -
Journal of Advanced Research Feb 2022Protein aggregation and deposition of uniformly arranged amyloid fibrils in the form of plaques or amorphous aggregates is characteristic of amyloid diseases. The... (Review)
Review
INTRODUCTION
Protein aggregation and deposition of uniformly arranged amyloid fibrils in the form of plaques or amorphous aggregates is characteristic of amyloid diseases. The accumulation and deposition of proteins result in toxicity and cause deleterious effects on affected individuals known as amyloidosis. There are about fifty different proteins and peptides involved in amyloidosis including neurodegenerative diseases and diseases affecting vital organs. Despite the strenuous effort to find a suitable treatment option for these amyloid disorders, very few compounds had made it to unsuccessful clinical trials. It has become a compelling challenge to understand and manage amyloidosis with the increased life expectancy and ageing population.
OBJECTIVE
While most of the currently available literature and knowledge base focus on the amyloid inhibitory mechanism as a treatment option, it is equally important to organize and understand amyloid disaggregation strategies. Disaggregation strategies are important and crucial as they are present innately functional in many living systems and dissolution of preformed amyloids may provide a direct benefit in many pathological conditions. In this review, we have compiled the known amyloid disaggregation mechanism, interactions, and possibilities of using disaggregases as a treatment option for amyloidosis.
METHODS
We have provided the structural details using protein-ligand docking models to visualize the interaction between these disaggregases with amyloid fibrils and their respective proposed amyloid disaggregation mechanisms.
RESULTS
After reviewing and comparing the different amyloid disaggregase systems and their proposed mechanisms, we presented two different hypotheses for ATP independent disaggregases using L-PGDS as a model.
CONCLUSION
Finally, we have highlighted the importance of understanding the underlying disaggregation mechanisms used by these chaperones and organic compounds before the implementation of these disaggregases as a potential treatment option for amyloidosis.
Topics: Amyloid; Amyloidogenic Proteins; Amyloidosis; Humans; Molecular Chaperones; Protein Aggregates
PubMed: 35127169
DOI: 10.1016/j.jare.2021.05.007 -
Journal of Colloid and Interface Science Jul 2023Amyloid fibrils from inexpensive food proteins and nanocellulose are renewable and biodegradable materials with broad ranging applications, such as water purification,...
Amyloid fibrils from inexpensive food proteins and nanocellulose are renewable and biodegradable materials with broad ranging applications, such as water purification, bioplastics and biomaterials. To improve the mechanical properties of hybrid amyloid-nanocellulose materials, their colloidal interactions need to be understood and tuned. A combination of turbidity and zeta potential measurements, rheology and atomic force microscopy point to the importance of electrostatic interactions. These interactions lead to entropy-driven polyelectrolyte complexation for positively charged hen egg white lysozyme (HEWL) amyloids with negatively charged nanocellulose. The complexation increased the elasticity of the amyloid network by cross-linking individual fibrils. Scaling laws suggest different contributions to elasticity depending on nanocellulose morphology: cellulose nanocrystals induce amyloid bundling and network formation, while cellulose nanofibrils contribute to a second network. The contribution of the amyloids to the elasticity of the entire network structure is independent of nanocellulose morphology and agrees with theoretical scaling laws. Finally, strong and almost transparent hybrid amyloid-nanocellulose gels were prepared in a slow self-assembly started from repulsive co-dispersions above the isoelectric point of the amyloids, followed by dialysis to decrease the pH and induce amyloid-nanocellulose attraction and cross-linking. In summary, the gained knowledge on colloidal interactions provides an important basis for the design of functional biohybrid materials based on these two biopolymers.
Topics: Amyloid; Amyloidogenic Proteins; Cellulose
PubMed: 36934581
DOI: 10.1016/j.jcis.2023.03.002 -
Cold Spring Harbor Perspectives in... Dec 2019When protein/peptides aggregate, they usually form the amyloid state consisting of cross β-sheet structure built by repetitively stacked β-strands forming long... (Review)
Review
When protein/peptides aggregate, they usually form the amyloid state consisting of cross β-sheet structure built by repetitively stacked β-strands forming long fibrils. Amyloids are usually associated with disease including Alzheimer's. However, amyloid has many useful features. It efficiently transforms protein from the soluble to the insoluble state in an essentially two-state process, while its repetitive structure provides high stability and a robust prion-like replication mechanism. Accordingly, amyloid is used by nature in multifaceted and ingenious ways of life, ranging from bacteria and fungi to mammals. These include (1) Structure: Templating for small chemical molecules (Pmel17), biofilm formation in bacteria (curli), assisting aerial hyphae formation in streptomycetes (chaplins) or monolayer formation at a surface (hydrophobins). (2) Reservoirs: A storage state for peptide/proteins to protect them from their surroundings or vice versa (storage of peptide hormones in mammalian secretory granules or major basic protein in eosinophils). (3) Information carriers: The fungal immune system (HET-s prion in , yeast prions) or long-term memory (e.g., mnemons in yeast, cytoplasmic polyadenylation element-binding protein in aplysia). Aggregation is also used to (4) "suppress" the function of the soluble protein (e.g., Cdc19 in yeast stress granules), or (5) "signaling" through formation of oligomers (e.g., HET-s prion, necroptosis-related proteins RIP1/RIP3). This review summarizes current knowledge on functional amyloids with a focus on the amyloid systems curli in bacteria, HET-s prion in , and peptide hormone storage in mammals together with an attempt to highlight differences between functional and disease-associated amyloids.
Topics: Amyloid; Bacteria; Fungi; Structure-Activity Relationship
PubMed: 31088827
DOI: 10.1101/cshperspect.a033860 -
The FEBS Journal Apr 2022Amyloid aggregation results from the self-assembly of identical aggregation-prone sequences into cross-beta-sheet structures. The process is best known for its... (Review)
Review
Amyloid aggregation results from the self-assembly of identical aggregation-prone sequences into cross-beta-sheet structures. The process is best known for its association with a wide range of human pathologies but also as a functional mechanism in all kingdoms of life. Less well elucidated is the role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease. We here review current data with a focus on neurodegenerative amyloid-associated diseases. Evidence indicates that heterotypic interactions occur in a wide range of amyloid processes and that these interactions modify fundamental aspects of amyloid aggregation including seeding, aggregation rates and toxicity. More work is required to understand the mechanistic origin of these interactions, but current understanding suggests that both supersaturation and sequence-specific binding can contribute to heterotypic amyloid interactions. Further unravelling these mechanisms may help to answer outstanding questions in the field including the selective vulnerability of cells types and tissues and the stereotypical spreading patterns of amyloids in disease.
Topics: Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Humans; Neurodegenerative Diseases
PubMed: 33460517
DOI: 10.1111/febs.15719 -
Microbiology Spectrum Dec 2016Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi),... (Review)
Review
Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary β-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the "protein-only" nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms.
Topics: Amyloid; Fungal Proteins; Fungi; Prions
PubMed: 28087950
DOI: 10.1128/microbiolspec.FUNK-0029-2016 -
Applied Microbiology and Biotechnology Dec 2022Microbe (including bacteria, fungi, and virus) infection in brains is associated with amyloid fibril deposit and neurodegeneration. Increasing findings suggest that... (Review)
Review
Microbe (including bacteria, fungi, and virus) infection in brains is associated with amyloid fibril deposit and neurodegeneration. Increasing findings suggest that amyloid proteins, like Abeta (Aβ), are important innate immune effectors in preventing infections. In some previous studies, amyloid peptides have been linked to antimicrobial peptides due to their common mechanisms in membrane-disruption ability, while the other mechanisms of bactericidal protein aggregation and protein function knockdown are less discussed. Besides, another important function of amyloid peptides in pathogen agglutination is rarely illustrated. In this review, we summarized and divided the different roles and mechanisms of amyloid peptides against microbes in antimicrobial activity and microbe agglutination activity. Besides, the range of amyloids' antimicrobial spectrum, the effectiveness of amyloid peptide states (monomers, oligomers, and fibrils), and cytotoxicity are discussed. The good properties of amyloid peptides against microbes might provide implications for the development of novel antimicrobial drug. KEY POINTS: • Antimicrobial and/or microbial agglutination is a characteristic of amyloid peptides. • Various mechanisms of amyloid peptides against microbes are discovered recently. • Amyloid peptides might be developed into novel antimicrobial drugs.
Topics: Amyloid; Amyloid beta-Peptides; Anti-Infective Agents; Amyloidogenic Proteins; Anti-Bacterial Agents; Agglutination
PubMed: 36322251
DOI: 10.1007/s00253-022-12246-w -
Biomolecules Dec 2021Amyloids are filamentous protein aggregates that are associated with a number of incurable diseases, termed amyloidoses. Amyloids can also manifest as infectious or... (Review)
Review
Amyloids are filamentous protein aggregates that are associated with a number of incurable diseases, termed amyloidoses. Amyloids can also manifest as infectious or heritable particles, known as prions. While just one prion is known in humans and animals, more than ten prion amyloids have been discovered in fungi. The propagation of fungal prion amyloids requires the chaperone Hsp104, though in excess it can eliminate some prions. Even though Hsp104 acts to disassemble prion fibrils, at normal levels it fragments them into multiple smaller pieces, which ensures prion propagation and accelerates prion conversion. Animals lack Hsp104, but disaggregation is performed by the same complement of chaperones that assist Hsp104 in yeast-Hsp40, Hsp70, and Hsp110. Exogenous Hsp104 can efficiently cooperate with these chaperones in animals and promotes disaggregation, especially of large amyloid aggregates, which indicates its potential as a treatment for amyloid diseases. However, despite the significant effects, Hsp104 and its potentiated variants may be insufficient to fully dissolve amyloid. In this review, we consider chaperone mechanisms acting to disassemble heritable protein aggregates in yeast and animals, and their potential use in the therapy of human amyloid diseases.
Topics: Amyloid; Animals; Fungal Proteins; Fungi; Heat-Shock Proteins; Humans; Models, Molecular; Prions; Protein Aggregates; Protein Conformation
PubMed: 34944528
DOI: 10.3390/biom11121884