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Molecules (Basel, Switzerland) Sep 2019Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid... (Review)
Review
Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer's disease (AD), Parkinson's disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways-including protein synthesis, quality control, and clearance-which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.
Topics: Amyloid; Amyloidogenic Proteins; Animals; Apoptosis; Autophagy; Biomarkers; Disease Susceptibility; Humans; Neurodegenerative Diseases; Protein Aggregates; Protein Aggregation, Pathological; Signal Transduction
PubMed: 31527516
DOI: 10.3390/molecules24183372 -
International Journal of Molecular... Aug 2021Amyloids are supramolecular assemblies composed of polypeptides stabilized by an intermolecular beta-sheet core. These misfolded conformations have been traditionally... (Review)
Review
Amyloids are supramolecular assemblies composed of polypeptides stabilized by an intermolecular beta-sheet core. These misfolded conformations have been traditionally associated with pathological conditions such as Alzheimer's and Parkinson´s diseases. However, this classical paradigm has changed in the last decade since the discovery that the amyloid state represents a universal alternative fold accessible to virtually any polypeptide chain. Moreover, recent findings have demonstrated that the amyloid fold can serve as catalytic scaffolds, creating new opportunities for the design of novel active bionanomaterials. Here, we review the latest advances in this area, with particular emphasis on the design and development of catalytic amyloids that exhibit hydrolytic activities. To date, three different types of activities have been demonstrated: esterase, phosphoesterase and di-phosphohydrolase. These artificial hydrolases emerge upon the self-assembly of small peptides into amyloids, giving rise to catalytically active surfaces. The highly stable nature of the amyloid fold can provide an attractive alternative for the design of future synthetic hydrolases with diverse applications in the industry, such as the in situ decontamination of xenobiotics.
Topics: Amyloid; Animals; Catalytic Domain; Humans; Hydrolases
PubMed: 34502074
DOI: 10.3390/ijms22179166 -
Methods (San Diego, Calif.) Apr 2018The amyloid fold is structurally characterized by a typical cross-β architecture, which is under debate to represent an energy-favourable folding state that many... (Review)
Review
The amyloid fold is structurally characterized by a typical cross-β architecture, which is under debate to represent an energy-favourable folding state that many globular or natively unfolded proteins can adopt. Being initially solely associated with amyloid fibrils observed in the propagation of several neurodegenerative disorders, the discovery of non-pathological (or "functional") amyloids in many native biological processes has recently further intensified the general interest invested in those cross-β supramolecular assemblies. The insoluble and non-crystalline nature of amyloid fibrils and their usually inhomogeneous appearance on the mesoscopic level pose a challenge to biophysical techniques aiming at an atomic-level structural characterization. Solid-state NMR spectroscopy (SSNMR) has granted breakthroughs in structural investigations on amyloid fibrils ranging from the assessment of the impact of polymorphism in disease development to the 3D atomic structure determination of amyloid fibrils. First landmark studies towards the characterization of atomic structures and interactions involving functional amyloids have provided new impulses in the understanding of the role of the amyloid fold in native biological functions. Over the last decade many strategies have been developed in protein isotope labelling, NMR resonance assignment, distance restraint determination and 3D structure calculation of amyloid fibrils based on SSNMR approaches. We will here discuss the emerging concepts and state-of-the-art methods related to the assessment of amyloid structures and interactions involving amyloid entities by SSNMR.
Topics: Amyloid; Humans; Isotope Labeling; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation
PubMed: 29627359
DOI: 10.1016/j.ymeth.2018.03.014 -
Cold Spring Harbor Perspectives in... Sep 2016Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to... (Review)
Review
Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to lethal, with specific effects dependent on the prion protein and the specific prion variant ("prion strain"). The prion amyloids of Sup35p, Ure2p, and Rnq1p are in-register, parallel, folded β-sheets, an architecture that naturally suggests a mechanism by which a protein can template its conformation, just as DNA or RNA templates its sequence. Prion propagation is critically affected by an array of chaperone systems, most notably the Hsp104/Hsp70/Hsp40 combination, which is responsible for generating new prion seeds from old filaments. The Btn2/Cur1 antiprion system cures most [URE3] prions that develop, and the Ssb antiprion system blocks [PSI+] generation.
Topics: Amyloid; Fungal Proteins; Prions; Yeasts
PubMed: 27481532
DOI: 10.1101/cshperspect.a023531 -
Biochimica Et Biophysica Acta. Proteins... Oct 2019The discovery of intrinsic disorderness in proteins and peptide regions has given a new and useful insight into the working of biological systems. Due to enormous... (Review)
Review
The discovery of intrinsic disorderness in proteins and peptide regions has given a new and useful insight into the working of biological systems. Due to enormous plasticity and heterogeneity, intrinsically disordered proteins or regions in proteins can perform myriad of functions. The flexibility in disordered proteins allows them to undergo conformation transition to form homopolymers of proteins called amyloids. Amyloids are highly structured protein aggregates associated with many neurodegenerative diseases. However, amyloids have gained much appreciation in recent years due to their functional roles. A functional amyloid fiber called curli is assembled on the bacterial cell surface as a part of the extracellular matrix during biofilm formation. The extracellular matrix that encases cells in a biofilm protects the cells and provides resistance against many environmental stresses. Several of the Csg (curli specific genes) proteins that are required for curli amyloid assembly are predicted to be intrinsically disordered. Therefore, curli amyloid formation is highly orchestrated so that these intrinsically disordered proteins do not inappropriately aggregate at the wrong time or place. The curli proteins are compartmentalized and there are chaperone-like proteins that prevent inappropriate aggregation and allow the controlled assembly of curli amyloids. Here we review the biogenesis of curli amyloids and the role that intrinsically disordered proteins play in the process.
Topics: Amyloid; Bacteria; Bacterial Physiological Phenomena; Bacterial Proteins; Biofilms; Protein Aggregates
PubMed: 31195143
DOI: 10.1016/j.bbapap.2019.05.010 -
Journal of Bacteriology Oct 2016Recent insights into bacterial biofilm matrix structures have induced a paradigm shift toward the recognition of amyloid fibers as common building block structures that... (Review)
Review
Recent insights into bacterial biofilm matrix structures have induced a paradigm shift toward the recognition of amyloid fibers as common building block structures that confer stability to the exopolysaccharide matrix. Here we describe the functional amyloid systems related to biofilm matrix formation in both Gram-negative and Gram-positive bacteria and recent knowledge regarding the interaction of amyloids with other biofilm matrix components such as extracellular DNA (eDNA) and the host immune system. In addition, we summarize the efforts to identify compounds that target amyloid fibers for therapeutic purposes and recent developments that take advantage of the amyloid structure to engineer amyloid fibers of bacterial biofilm matrices for biotechnological applications.
Topics: Amyloid; Bacterial Proteins; Biofilms; DNA, Bacterial; Gene Expression Regulation, Bacterial
PubMed: 27185827
DOI: 10.1128/JB.00122-16 -
Prion 2018Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has... (Review)
Review
Protein misfolding and aggregation into highly ordered fibrillar structures have been traditionally associated with pathological processes. Nevertheless, nature has taken advantage of the particular properties of amyloids for functional purposes, like in the protection of organisms against environmental changing conditions. Over the last decades, these fibrillar structures have inspired the design of new nanomaterials with intriguing applications in biomedicine and nanotechnology such as tissue engineering, drug delivery, adhesive materials, biodegradable nanocomposites, nanowires or biosensors. Prion and prion-like proteins, which are considered a subclass of amyloids, are becoming ideal candidates for the design of new and tunable nanomaterials. In this review, we discuss the particular properties of this kind of proteins, and the current advances on the design of new materials based on prion sequences.
Topics: Amyloid; Animals; Biosensing Techniques; Drug Design; Humans; Nanomedicine; Nanostructures; Prions; Tissue Engineering
PubMed: 30196749
DOI: 10.1080/19336896.2018.1521235 -
International Journal of Molecular... May 2021Proteolytic enzymes are known to be involved in the formation and degradation of various monomeric proteins, but the effect of proteases on the ordered protein...
Proteolytic enzymes are known to be involved in the formation and degradation of various monomeric proteins, but the effect of proteases on the ordered protein aggregates, amyloid fibrils, which are considered to be extremely stable, remains poorly understood. In this work we study resistance to proteolytic degradation of lysozyme amyloid fibrils with two different types of morphology and beta-2-microglobulun amyloids. We showed that the proteolytic enzyme of the pancreas, trypsin, induced degradation of amyloid fibrils, and the mechanism of this process was qualitatively the same for all investigated amyloids. At the same time, we found a dependence of efficiency and rate of fibril degradation on the structure of the amyloid-forming protein as well as on the morphology and clustering of amyloid fibrils. It was assumed that the discovered relationship between fibrils structure and the efficiency of their degradation by trypsin can become the basis of a new express method for the analysis of amyloids polymorphism. Unexpectedly lower resistance of both types of lysozyme amyloids to trypsin exposure compared to the native monomeric protein (which is not susceptible to hydrolysis) was attributed to the higher availability of cleavage sites in studied fibrils. Another intriguing result of the work is that the cytotoxicity of amyloids treated with trypsin was not only failing to decline, but even increasing in the case of beta-2-microglobulin fibrils.
Topics: Amyloid; Amyloid beta-Peptides; Anilino Naphthalenesulfonates; Benzothiazoles; Fluorescent Dyes; HeLa Cells; Humans; Hydrogen-Ion Concentration; Hydrolysis; Muramidase; Proteolysis; Trypsin; beta 2-Microglobulin
PubMed: 34063223
DOI: 10.3390/ijms22094828 -
Molecules (Basel, Switzerland) Jan 2019Amyloid diseases, including neurodegenerative diseases such as Alzheimer's and Parkinson's, are linked to a poorly understood progression of protein misfolding and... (Review)
Review
Amyloid diseases, including neurodegenerative diseases such as Alzheimer's and Parkinson's, are linked to a poorly understood progression of protein misfolding and aggregation events that culminate in tissue-selective deposition and human pathology. Elucidation of the mechanistic details of protein aggregation and the structural features of the aggregates is critical for a comprehensive understanding of the mechanisms of protein oligomerization and fibrillization. Vibrational spectroscopies, such as Fourier transform infrared (FTIR) and Raman, are powerful tools that are sensitive to the secondary structure of proteins and have been widely used to investigate protein misfolding and aggregation. We address the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils. In particular, introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain, have greatly expanded the ability of vibrational spectroscopy to obtain site-specific structural and dynamic information. The applications of these methods in recent studies of protein aggregation are also reviewed.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Humans; Islet Amyloid Polypeptide; Isotope Labeling; Models, Molecular; Parkinson Disease; Protein Multimerization; Protein Structure, Secondary; Spectrum Analysis; Vibration
PubMed: 30621325
DOI: 10.3390/molecules24010186 -
Cellular and Molecular Life Sciences :... Dec 2021A review of the multidisciplinary scientific literature reveals a large variety of amyloid-β (Aβ) oligomeric species, differing in molecular weight, conformation and... (Review)
Review
A review of the multidisciplinary scientific literature reveals a large variety of amyloid-β (Aβ) oligomeric species, differing in molecular weight, conformation and morphology. These species, which may assemble via either on- or off-aggregation pathways, exhibit differences in stability, function and neurotoxicity, according to different experimental settings. The conformations of the different Aβ species are stabilized by intra- and inter-molecular hydrogen bonds and by electrostatic and hydrophobic interactions, all depending on the chemical and physical environment (e.g., solvent, ions, pH) and interactions with other molecules, such as lipids and proteins. This complexity and the lack of a complete understanding of the relationship between the different Aβ species and their toxicity is currently dictating the nature of the inhibitor (or inducer)-based approaches that are under development for interfering with (or inducing) the formation of specific species and Aβ oligomerization, and for interfering with the associated downstream neurotoxic effects. Here, we review the principles that underlie the involvement of different Aβ oligomeric species in neurodegeneration, both in vitro and in preclinical studies. In addition, we provide an overview of the existing inhibitors (or inducers) of Aβ oligomerization that serve as potential therapeutics for neurodegenerative diseases. The review, which covers the exciting studies that have been published in the past few years, comprises three main parts: 1) on- and off-fibrillar assembly mechanisms and Aβ structural polymorphism; 2) interactions of Aβ with other molecules and cell components that dictate the Aβ aggregation pathway; and 3) targeting the on-fibrillar Aβ assembly pathway as a therapeutic approach.
Topics: Amyloid; Amyloid beta-Peptides; Humans; Neurodegenerative Diseases; Peptide Fragments; Protein Aggregation, Pathological; Protein Conformation
PubMed: 34643743
DOI: 10.1007/s00018-021-03954-z