scholarly journals Concentration-dependent polymorphism of insulin amyloid fibrils

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8208 ◽  
Author(s):  
Andrius Sakalauskas ◽  
Mantas Ziaunys ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disorders ◽  
Protein Concentration ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Drug Research ◽  
Amyloid Proteins ◽  
Disease Mechanisms ◽  
Slow Progress ◽  
Self Replication

Protein aggregation into highly structured fibrils has long been associated with several neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease. Polymorphism of amyloid fibrils increases the complexity of disease mechanisms and may be one of the reasons for the slow progress in drug research. Here we report protein concentration as another factor leading to polymorphism of insulin amyloid fibrils. Moreover, our data suggests that insulin amyloid conformation can self-replicate only via elongation, while seed-induced nucleation will lead to environment-defined conformation of fibrils. As similar observations were already described for a couple of other amyloid proteins, we suggest it to be a generic mechanism for self-replication of different amyloid fibril conformations.

scholarly journals Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation

2020 ◽  
Author(s):  
Tien M. Phan ◽  
Jeremy D. Schmit
Keyword(s):  
Phase Transitions ◽  
Neurodegenerative Disorders ◽  
Protein Concentration ◽  
Amyloid Fibrils ◽  
Amyloid Aggregation ◽  
Binary Variable ◽  
Conformational Disorder ◽  
Binding Surface ◽  
Elongation Phase ◽  
Degree Of Order

The formation of amyloid fibrils in Alzheimer’s disease and other neurodegenerative disorders is limited by a slow nucleation step due to the entropic cost to initiate the ordered cross-β structure. While the barrier can be lowered if the molecules maintain conformational disorder, poorly ordered clusters provide a poor binding surface for new molecules. To understand these opposing factors, we used all-atom simulations to parameterize a lattice model that treats each amino acid as a binary variable with β-sheet and non-β states. We find that the optimal degree of order in a nucleus depends on protein concentration. Low concentration systems require more ordered nuclei to capture infrequent monomer attachments. The nucleation phase transitions to the elongation phase when the β-sheet core becomes large enough to overcome the initiation cost, at which point further ordering becomes favorable and the nascent fibril efficiently captures new molecules.

scholarly journals Role of Pre-molten Globule Structure in Protein Amyloid Fibril Formation

2019 ◽  
Vol 7 (1) ◽  
pp. 35-42
Author(s):  
Ali Es-haghi ◽  
Mahsa Jahedi Moghaddam ◽  
Koorosh Shahpasand
Keyword(s):  
Protein Aggregation ◽  
Protein Unfolding ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Molten Globule ◽  
Critical Event ◽  
Diabetic Mellitus ◽  
Native Conformation ◽  
Amyloid Fibril Formation

The conversion of a protein from its native conformation to the pathogenic form is a critical event in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s (AD), Parkinson’s, and Huntington’s diseases, along with type II diabetic mellitus. Although there are several reports on the mechanism of protein aggregation, the actual conformation playing a part in the pathogenicity is yet unclear. Accordingly, the present study summarizes the early pathogenic conformation resulting in several protein aggregations. It is well-documented that a pre-molten globule (MG) structure appears at the early stages of some proteins. Pre-MG is one of the intermediate structures, which is formed during some protein unfolding processes. In addition, it is shown that the pre-molten structure is more flexible than the mature MG one and thus, protein easily rearranges to form amyloid fibrils in this conformation. Therefore, protein aggregation is halted by preventing the pre-MG structure. The strategy of protein aggregation prevention has profound implications in fighting the devastating disorder.

scholarly journals Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid.

1976 ◽  
Vol 143 (4) ◽  
pp. 993-998 ◽  
Author(s):  
K Sletten ◽  
P Westermark ◽  
J B Natvig
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Medullary Carcinoma ◽  
Low Molecular Weight ◽  
Human Calcitonin ◽  
Amyloid Proteins ◽  
Weight Protein ◽  
Low Molecular Weight Protein ◽  
Cyanogen Bromide Fragment

Amyloid fibrils were studied from two different tissues of medullary carcinoma of the thyroid (MCT). The fibrils mainly consisted of a low molecular weight protein, AMCT, which was immunologically distinct and did not react with various antisera against known amyloid fibril proteins. A specific antiserum raised against the MCT amyloid proteins gave a reaction of identity with the degraded MCT amyloid fibrils from two patients, as well as with the isolated AMCT protein, but showed no reaction with other known amyloid proteins. The AMCT protein had a blocked N terminus, but the sequence analysis of a cyanogen bromide fragment revealed identity with human calcitonin in the 11 positions studied. Although the amino acid composition was similar, there were also distinct differences, and the mol wt of 5,700 daltons was considerably larger than that of calcitonin. For these reasons the AMCT protein may represent a prohormone of calcitonin.

scholarly journals Liquid condensates increase potency of amyloid fibril inhibitors

2020 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
L. Mahadevan ◽  
Christoph A. Weber
Keyword(s):  
Phase Separation ◽  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Amyloid Formation ◽  
Physiological Processes ◽  
Parkinson’S Diseases ◽  
Spatio Temporal ◽  
Liquid Condensate

In living cells, liquid condensates form in the cytoplasm and nucleoplasm via phase separation and regulate physiological processes. They also regulate aberrant aggregation of amyloid fibrils, a process linked to Alzheimer’s and Parkinson’s diseases. In the absence of condensates it has been shown that amyloid aggregation can be inhibited by molecular chaperones and rationally designed drugs. However it remains unknown how this drug- or chaperone-mediated inhibition of amyloid fibril aggregation is affected by phase-separated condensates. Here we study the interplay between protein aggregation, its inhibition and liquid-liquid phase separation. Our key finding is that the potency of inhibitors of amyloid formation can be strongly enhanced. We show that the corresponding mechanism relies on the colocalization of inhibitors and aggregates inside the liquid condensate. We provide experimentally testable physicochemical conditions under which the increase of inhibitor potency is most pronounced. Our work highlights the role of spatio-temporal heterogeneity in curtailing aberrant protein aggregation and suggests design principles for amyloid inhibitors accounting for partitioning of drugs into liquid condensates.

scholarly journals Exploring the potential of deep-blue autofluorescence for monitoring amyloid fibril formation and dissociation

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7554
Author(s):  
Mantas Ziaunys ◽  
Tomas Sneideris ◽  
Vytautas Smirnovas
Keyword(s):  
Neurodegenerative Disorders ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Fibril Formation ◽  
Amyloid Formation ◽  
Amyloid Aggregation ◽  
Deep Blue ◽  
Amyloid Fibril Formation ◽  
Kinetics Of ◽  
Kinetics Of Fibril Formation

Protein aggregation into amyloid fibrils has been linked to multiple neurodegenerative disorders. Determining the kinetics of fibril formation, as well as their structural stability are important for the mechanistic understanding of amyloid aggregation. Tracking both fibril association and dissociation is usually performed by measuring light scattering of the solution or fluorescence of amyloid specific dyes, such as thioflavin-T. A possible addition to these methods is the recently discovered deep-blue autofluorescence (dbAF), which is linked to amyloid formation. In this work we explore the potential of this phenomenon to monitor amyloid fibril formation and dissociation, as well as show its possible relation to fibril size rather than amyloid structure.

scholarly journals Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils

2021 ◽  
Vol 22 (10) ◽  
pp. 5075
Author(s):  
Mantas Ziaunys ◽  
Andrius Sakalauskas ◽  
Kamile Mikalauskaite ◽  
Ruta Snieckute ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Prion Protein ◽  
Amyloid Fibrils ◽  
Prion Diseases ◽  
Morphological Properties ◽  
Large Sample Size ◽  
Structural Variations ◽  
Temperature Dependent ◽  
Protein Fibrils ◽  
Propagation Properties

Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules.

scholarly journals The Ultrastructure of Tissue Damage by Amyloid Fibrils

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4611
Author(s):  
Haruki Koike ◽  
Masahisa Katsuno
Keyword(s):  
Tissue Damage ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Prion Diseases ◽  
Nerve Biopsy ◽  
Al Amyloidosis ◽  
Amyloid Fibril Formation ◽  
Autopsy Specimens ◽  
Fibril Aggregates ◽  
Interfering Rna

Amyloidosis is a group of diseases that includes Alzheimer’s disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: 1) reducing or preventing the production of causative proteins; 2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or 3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.

Inhibition of Amyloid Fibril Growth and Dissolution of Amyloid Fibrils by Curcumin-Gold Nanoparticles

2014 ◽  
Vol 20 (20) ◽  
pp. 6184-6191 ◽  
Author(s):  
Sharbari Palmal ◽  
Amit Ranjan Maity ◽  
Brijesh Kumar Singh ◽  
Sreetama Basu ◽  
Nihar R. Jana ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Amyloid Fibrils ◽  
Amyloid Fibril

scholarly journals Molecular dynamics simulations of mechanical failure in polymorphic arrangements of amyloid fibrils containing structural defects

2013 ◽  
Vol 4 ◽  
pp. 429-440 ◽  
Author(s):  
Hlengisizwe Ndlovu ◽  
Alison E Ashcroft ◽  
Sheena E Radford ◽  
Sarah A Harris
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Steered Molecular Dynamics ◽  
Mechanical Failure ◽  
Structural Defects ◽  
Dynamics Simulations

We examine how the different steric packing arrangements found in amyloid fibril polymorphs can modulate their mechanical properties using steered molecular dynamics simulations. Our calculations demonstrate that for fibrils containing structural defects, their ability to resist force in a particular direction can be dominated by both the number and molecular details of the defects that are present. The simulations thereby suggest a hierarchy of factors that govern the mechanical resilience of fibrils, and illustrate the general principles that must be considered when quantifying the mechanical properties of amyloid fibres containing defects.

scholarly journals The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid

2021 ◽  
Vol 118 (3) ◽  
pp. e2014442118
Author(s):  
Nir Salinas ◽  
Einav Tayeb-Fligelman ◽  
Massimo D. Sammito ◽  
Daniel Bloch ◽  
Raz Jelinek ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Membrane Damage ◽  
Fibril Formation ◽  
Regulation Mechanism ◽  
Bacterial Cells ◽  
Amyloid Fibril Formation ◽  
Β Amyloid ◽  
Β Sheets

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

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