scholarly journals SERF engages in a fuzzy complex that accelerates primary nucleation of amyloid proteins

2019 ◽  
Vol 116 (46) ◽  
pp. 23040-23049 ◽  
Author(s):  
Ben A. Meinen ◽  
Varun V. Gadkari ◽  
Frederick Stull ◽  
Brandon T. Ruotolo ◽  
James C. A. Bardwell
Keyword(s):  
Ion Mobility ◽  
Amyloid Fibrils ◽  
Structural Diversity ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Disordered Protein ◽  
Primary Nucleation ◽  
Age Related ◽  
Related Proteins ◽  
High Degree

The assembly of small disordered proteins into highly ordered amyloid fibrils in Alzheimer’s and Parkinson’s patients is closely associated with dementia and neurodegeneration. Understanding the process of amyloid formation is thus crucial in the development of effective treatments for these devastating neurodegenerative diseases. Recently, a tiny, highly conserved and disordered protein called SERF was discovered to modify amyloid formation in Caenorhabditis elegans and humans. Here, we use kinetics measurements and native ion mobility-mass spectrometry to show that SERF mainly affects the rate of primary nucleation in amyloid formation for the disease-related proteins Aβ40 and α-synuclein. SERF’s high degree of plasticity enables it to bind various conformations of monomeric Aβ40 and α-synuclein to form structurally diverse, fuzzy complexes. This structural diversity persists into early stages of amyloid formation. Our results suggest that amyloid nucleation is considerably more complex than age-related conversion of Aβ40 and α-synuclein into single amyloid-prone conformations.

scholarly journals Cross-talk between individual phenol-soluble modulins in Staphylococcus aureus biofilm enables rapid and efficient amyloid formation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Masihuz Zaman ◽  
Maria Andreasen
Keyword(s):  
Staphylococcus Aureus ◽  
Self Assembly ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Amyloid Formation ◽  
Secondary Nucleation ◽  
Primary Nucleation ◽  
Functional Amyloids ◽  
High Degree

The infective ability of the opportunistic pathogen Staphylococcus aureus, recognized as the most frequent cause of biofilm-associated infections, is associated with biofilm-mediated resistance to host immune response. Phenol-soluble modulins (PSM) comprise the structural scaffold of S. aureus biofilms through self-assembly into functional amyloids, but the role of individual PSMs during biofilm formation remains poorly understood and the molecular pathways of PSM self-assembly are yet to be identified. Here we demonstrate high degree of cooperation between individual PSMs during functional amyloid formation. PSMα3 initiates the aggregation, forming unstable aggregates capable of seeding other PSMs resulting in stable amyloid structures. Using chemical kinetics we dissect the molecular mechanism of aggregation of individual PSMs showing that PSMα1, PSMα3 and PSMβ1 display secondary nucleation whereas PSMβ2 aggregates through primary nucleation and elongation. Our findings suggest that various PSMs have evolved to ensure fast and efficient biofilm formation through cooperation between individual peptides.

scholarly journals Multistep changes in amyloid structure that are induced by cross-seeding on a rugged energy landscape

2020 ◽  
Author(s):  
Keisuke Yuzu ◽  
Naoki Yamamoto ◽  
Masahiro Noji ◽  
Masatomo So ◽  
Yuji Goto ◽  
...  
Keyword(s):  
Structural Changes ◽  
Amyloid Fibrils ◽  
Energy Landscape ◽  
Structural Diversity ◽  
Bovine Insulin ◽  
Amyloid Formation ◽  
Heterologous Proteins ◽  
Iodine Staining ◽  
Dependent Growth ◽  
Value Decomposition

ABSTRACTAmyloid fibrils are aberrant protein aggregates associated with various amyloidoses and neurodegenerative diseases. It is recently indicated that structural diversity of amyloid fibrils often results in different pathological phenotypes including cytotoxicity and infectivity. The diverse structures are predicted to propagate by seed-dependent growth, which is one of the characteristic properties of amyloid fibrils. However, much remains unknown regarding how exactly the amyloid structures are inherited to subsequent generations by seeding reaction. Here, we investigated the behaviors of self- and cross-seeding of amyloid fibrils of human and bovine insulin in terms of thioflavin T fluorescence, morphology, secondary structure, and iodine staining. Insulin amyloid fibrils exhibited different structures depending on species, and each of which replicated in self-seeding. In contrast, gradual structural changes were observed in cross-seeding, and a new-type amyloid structure with distinct morphology and cytotoxicity was formed when human insulin was seeded with bovine insulin fibrils. Remarkably, iodine staining tracked changes in amyloid structure sensitively, and singular value decomposition (SVD) analysis of the UV-Vis absorption spectra of the fibril-bound iodine has revealed the presence of one or more intermediate metastable states during the structural changes. From these findings, we propose a propagation scheme with multistep structural changes in cross-seeding between two heterologous proteins, which is accounted for as a consequence of the rugged energy landscape of amyloid formation.

scholarly journals The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation

2020 ◽  
Author(s):  
Anita Pras ◽  
Bert Houben ◽  
Francesco A. Aprile ◽  
Renée Seinstra ◽  
Rodrigo Gallardo ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Structural Changes ◽  
Colloidal Stability ◽  
Positive Charge ◽  
Amyloid Formation ◽  
Related Protein ◽  
Age Related ◽  
Related Proteins ◽  
Protein Toxicity ◽  
Charge Interactions

AbstractWhile aggregation-prone proteins are known to accelerate ageing and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A and SERF2 have recently been identified as cellular modifiers of such cytotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with specific patterns of negatively charged and hydrophobic, aromatic amino acids. The absence of such patterns, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In a protein aggregation model in the nematode C. elegans, protein aggregation was suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that charge interactions are required for MOAG-4 and SERF2 to promote aggregation. Such charged interactions might accelerate the primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our finding that negatively charged segments are overrepresented in amyloid-forming proteins suggests that inhibition of charge interactions deserves exploration as a strategy to target age-related protein toxicity.Significance StatementHow aging causes relatively common diseases such as Alzheimer’s and Parkinson’s is still a mystery. Since toxic structural changes in proteins are likely to be responsible, we investigated biological mechanisms that could drive such changes. We made use of a modifying factor called SERF2, which accelerates structural changes and aggregation of several disease-related proteins. Through a peptide-binding screen, we found that SERF2 acts on negatively charged protein regions. The abundance of such regions in the disease-related proteins explains why SERF has its effect. Removing positive charge in SERF was sufficient to suppress protein aggregation in models for disease. We propose that blocking charge-interactions with SERF or other modifiers could serve as a general approach to treat age-related protein toxicity.

scholarly journals Amyloid formation of fish β-parvalbumin involves primary nucleation triggered by disulfide-bridged protein dimers

2020 ◽  
Vol 117 (45) ◽  
pp. 27997-28004
Author(s):  
Tony E. R. Werner ◽  
David Bernson ◽  
Elin K. Esbjörner ◽  
Sandra Rocha ◽  
Pernilla Wittung-Stafshede
Keyword(s):  
Disulfide Bonds ◽  
Amyloid Fibrils ◽  
Kinetic Mechanism ◽  
Amyloid Formation ◽  
Structural Conversion ◽  
Aggregation Mechanism ◽  
Primary Nucleation ◽  
Protein Dimers ◽  
Induced Aggregation

Amyloid formation involves the conversion of soluble protein species to an aggregated state. Amyloid fibrils of β-parvalbumin, a protein abundant in fish, act as an allergen but also inhibit the in vitro assembly of the Parkinson protein α-synuclein. However, the intrinsic aggregation mechanism of β-parvalbumin has not yet been elucidated. We performed biophysical experiments in combination with mathematical modeling of aggregation kinetics and discovered that the aggregation of β-parvalbumin is initiated by the formation of dimers stabilized by disulfide bonds and then proceeds via primary nucleation and fibril elongation processes. Dimer formation is accelerated by H2O2and hindered by reducing agents, resulting in faster and slower aggregation rates, respectively. Purified β-parvalbumin dimers readily assemble into amyloid fibrils with similar morphology as those formed when starting from monomer solutions. Furthermore, addition of preformed dimers accelerates the aggregation reaction of monomers. Aggregation of purified β-parvalbumin dimers follows the same kinetic mechanism as that of monomers, implying that the rate-limiting primary nucleus is larger than a dimer and/or involves structural conversion. Our findings demonstrate a folded protein system in which spontaneously formed intermolecular disulfide bonds initiate amyloid fibril formation by recruitment of monomers. This dimer-induced aggregation mechanism may be of relevance for human amyloid diseases in which oxidative stress is often an associated hallmark.

Ion Mobility—Mass Spectrometry-Based Screening for Inhibition of α-Synuclein Aggregation

2015 ◽  
Vol 21 (3) ◽  
pp. 255-264 ◽  
Author(s):  
Yanqin Liu ◽  
Michael Graetz ◽  
Lam Ho ◽  
Tara L. Pukala
Keyword(s):  
Mass Spectrometry ◽  
Conformational Changes ◽  
Ion Mobility ◽  
Amyloid Fibrils ◽  
Therapeutic Agents ◽  
Ion Mobility Mass Spectrometry ◽  
Amyloid Formation ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Screening Approaches

Aberrant protein folding and formation of amyloid fibrils are associated with numerous debilitating human diseases, for which there are currently no suitable therapeutic treatments. For instance, Parkinson's disease is characterised pathologically by the intraneural accumulation of the amyloid protein α-synuclein. In order to search for new therapeutic agents that are effective in preventing the early conformational changes that precede protein aggregation, it is necessary to devise new analytical screening approaches. Here we demonstrate the use of ion mobility–mass spectrometry for screening of molecules capable of inhibiting the misfolding and aggregation of α-synuclein (specifically, the A53T human mutant). Importantly, this assay allows for the analysis of conformational changes that precede aggregation, and therefore is unique in its ability to identify inhibitors working at the earliest stages of amyloid formation. In addition, we use complementary mass spectrometry methods to probe selected protein–ligand interactions responsible for fibril inhibition.

scholarly journals Apomorphine Targets the Pleiotropic Bacterial Regulator Hfq

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 257
Author(s):  
Florian Turbant ◽  
David Partouche ◽  
Omar El Hamoui ◽  
Sylvain Trépout ◽  
Théa Legoubey ◽  
...  
Keyword(s):  
Small Rnas ◽  
Antibacterial Agents ◽  
Amyloid Fibrils ◽  
Noncoding Rnas ◽  
Amyloid Formation ◽  
Gram Negative Bacteria ◽  
Translation Efficiency ◽  
Gram Negative ◽  
Bacterial Adaptation ◽  
E Coli

Hfq is a bacterial regulator with key roles in gene expression. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, thanks to its binding to small regulatory noncoding RNAs. This property is of primary importance for bacterial adaptation and survival in hosts. Small RNAs and Hfq are, for instance, involved in the response to antibiotics. Previous work has shown that the E. coli Hfq C-terminal region (Hfq-CTR) self-assembles into an amyloid structure. It was also demonstrated that the green tea compound EpiGallo Catechin Gallate (EGCG) binds to Hfq-CTR amyloid fibrils and remodels them into nonamyloid structures. Thus, compounds that target the amyloid region of Hfq may be used as antibacterial agents. Here, we show that another compound that inhibits amyloid formation, apomorphine, may also serve as a new antibacterial. Our results provide an alternative in order to repurpose apomorphine, commonly used in the treatment of Parkinson’s disease, as an antibiotic to block bacterial adaptation to treat infections.

Age-Related Considerations in the Treatment of ADHD

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S23) ◽  
pp. 10-13 ◽  
Author(s):  
Jeffrey H. Newcorn
Keyword(s):  
Time Management ◽  
Task Completion ◽  
Occupational Performance ◽  
Social Situations ◽  
Attentional Function ◽  
Hyperactivity Disorder ◽  
Age Related ◽  
Adolescents And Adults ◽  
Core Symptoms ◽  
High Degree

Although the symptoms of attention-deficit/hyperactivity disorder (ADHD) can be found in many “normal” people, these symptoms are present to a greater extent in those affected by the disorder. In these patients, ADHD symptoms cause substantial functional impairment. Therefore, the goal of treatment is not simply to reduce core symptoms, but also to decrease the level of impairment caused by these symptoms.Common impairments in adolescents and adults include academic and occupational problems that are particularly evident in the context of tasks requiring a high degree of organization or attentional function. These impairments result in problems related to task completion, prioritizing work and other obligations, and time management, etc. These symptoms often impact successful completion of tasks in school or at work, and can also result in a variety of problems in initiating and managing relationships (Slide 1).Mood and anxiety disorders often co-occur with ADHD in adults. The accumulation of experiences related to impaired academic and/or occupational performance, and or persistent relationship problems, due to the symptoms of ADHD, can lead to either depressed mood or anxiety related to performance and/or social situations. Therefore, in treating adults with ADHD, reduction of those co-occurring symptom presentations is also an important goal.

Scaphechinus mirabilis extract effectively inhibits the proliferation of BPH-1 and LNCaP prostate epithelial cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Kyung-Hyun Kim ◽  
Geum-Lan Hong ◽  
Shanika Karunasagara ◽  
Ju-Young Jung
Keyword(s):  
Epithelial Cells ◽  
Sea Urchins ◽  
Specific Antigen ◽  
Marine Species ◽  
Lncap Cells ◽  
Caspase 9 ◽  
Scaphechinus Mirabilis ◽  
Age Related ◽  
Prostate Epithelial Cells ◽  
Related Proteins

Background: Benign prostatic hyperplasia (BPH) is an age-related disease characterized by progressive proliferation of prostate stromal and epithelial cells. While the precise etiology of BPH is still not clear, the proliferation of epithelial cells has been implicated in the development of the disease. Scaphechinus mirabilis (S. mirabilis) is a marine species belonging to the order Clypeasteroida, which contains flat, burrowing sea urchins. Objective: This study examined the effects of S. mirabilis extract on the proliferation of BPH-1 and LNCaP prostate epithelial cells. Methods: BPH-1 and LNCaP cells were cultured and treated with S. mirabilis extract (50, 100, and 200 μg/ml). The viability of cells treated with S. mirabilis extract was determined by the MTT assay. Results: Proliferation of BPH-1 and testosterone-induced LNCaP cells was inhibited by treatment with S. mirabilis extract. S. mirabilis extract suppressed the expression of androgen-related proteins, such as androgen receptor, prostate-specific antigen, and 5α-reductase 2. S. mirabilis extract inhibited testosterone-induced proliferation. Moreover, S. mirabilis extract induced apoptotic responses by regulating the expression of caspase-9, Bcl-2, and Bax. Conclusion: These findings suggest that S. mirabilis extract abrogated the expression of androgen-related proteins by inducing apoptotic responses, which could be valuable for the design of new therapeutic agents for the treatment of BPH.

Synthetic and Biological Attributes of Pyrimidine Derivatives: A Recent update

2021 ◽  
Vol 18 ◽  
Author(s):  
Meenu Devi ◽  
Shivangi Jaiswal ◽  
Sonika Jain ◽  
Navjeet Kaur ◽  
Jaya Dwivedi
Keyword(s):  
Biological Activities ◽  
Structural Diversity ◽  
Therapeutic Agents ◽  
Pyrimidine Derivatives ◽  
Diverse Range ◽  
Biological Attributes ◽  
Synthetic Approaches ◽  
High Degree ◽  
Therapeutic Activities ◽  
Anti Hiv

: Nitrogen-containing heterocycles attract the attention of chemists due to their multifarious activities. Amongst all, pyrimidine plays a central role and exhibits a broad spectrum of biological activities. Literature is replete with the various aspects of synthetic development in pyrimidine chemistry for a wide array of applications. It aroused our interest to compile various novel and efficient synthetic approaches towards the synthesis of pyrimidine and its derivatives. Pyrimidine derivatives are broadly useful as therapeutic agents, owing to their high degree of structural diversity. They have been recorded to possess a diverse range of therapeutic activities, viz. anticancer, anti-inflammatory, anti-HIV etc.

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