scholarly journals A molecular model of the surface-assisted protein aggregation process

2018 ◽  
Author(s):  
Y.G. Pan ◽  
S. Banerjee ◽  
K. Zagorski ◽  
L.S. Shlyakhtenko ◽  
A.B. Kolomeisky ◽  
...  
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Molecular Model ◽  
Critical Role ◽  
Experimental Studies ◽  
Cytosine Deaminase ◽  
Aggregation Process ◽  
Amyloidogenic Proteins ◽  
Low Concentrations ◽  
Kinetics Of

AbstractThe importance of cell surfaces in the self-assembly of proteins is widely accepted. One biologically significant event is the assembly of amyloidogenic proteins into aggregates, which leads to neurodegenerative disorders like Alzheimer’s and Parkinson’s. The interaction of amyloidogenic proteins with cellular membranes appears to dramatically facilitate the aggregation process. Recent findings indicate that, in the presence of surfaces, aggregation occurs at physiologically low concentrations, suggesting interaction with surfaces plays a critical role in the disease-prone aggregation process. However, the molecular mechanisms behind on-surface aggregation remain unclear. Here we provide a theoretical model that offers a molecular explanation. According to this model, monomers transiently immobilized to surfaces increase the local monomer protein concentration and thus work as nuclei to dramatically accelerate the entire aggregation process. This theory was verified by experimental studies, using mica surfaces, to examine the aggregation kinetics of amyloidogenic-synuclein protein (α-Syn) and non-amyloidogenic cytosine deaminase APOBEC3G (A3G).

scholarly journals Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

2014 ◽  
Vol 56 ◽  
pp. 167-180 ◽  
Author(s):  
Philipp Trepte ◽  
Nadine Strempel ◽  
Erich E. Wanker
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Cytoplasmic Inclusion ◽  
Spinocerebellar Ataxia Type ◽  
Neuronal Processes ◽  
Exon 1 ◽  
Novel Therapeutic Strategies

PolyQ (polyglutamine) diseases such as HD (Huntington's disease) or SCA1 (spinocerebellar ataxia type 1) are neurodegenerative disorders caused by abnormally elongated polyQ tracts in human proteins. PolyQ expansions promote misfolding and aggregation of disease-causing proteins, leading to the appearance of nuclear and cytoplasmic inclusion bodies in patient neurons. Several lines of experimental evidence indicate that this process is critical for disease pathogenesis. However, the molecular mechanisms underlying spontaneous polyQ-containing aggregate formation and the perturbation of neuronal processes are still largely unclear. The present chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing HTTex1 (huntingtin exon 1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed.

scholarly journals Slow Dissolution Kinetics of Model Peptide Fibrils

2020 ◽  
Vol 21 (20) ◽  
pp. 7671
Author(s):  
Mona Koder Hamid ◽  
Axel Rüter ◽  
Stefan Kuczera ◽  
Ulf Olsson
Keyword(s):  
Hydrogen Bonds ◽  
Self Assembly ◽  
Amyloid Fibrils ◽  
Dissolution Kinetics ◽  
Titration Calorimetry ◽  
Model Peptide ◽  
Rate Limiting Step ◽  
Low Concentrations ◽  
Peptide Fibrils ◽  
Kinetics Of

Understanding the kinetics of peptide self-assembly is important because of the involvement of peptide amyloid fibrils in several neurodegenerative diseases. In this paper, we have studied the dissolution kinetics of self-assembled model peptide fibrils after a dilution quench. Due to the low concentrations involved, the experimental method of choice was isothermal titration calorimetry (ITC). We show that the dissolution is a strikingly slow and reaction-limited process, that can be timescale separated from other rapid processes associated with dilution in the ITC experiment. We argue that the rate-limiting step of dissolution involves the breaking up of inter-peptide β–sheet hydrogen bonds, replacing them with peptide–water hydrogen bonds. Complementary pH experiments revealed that the self-assembly involves partial deprotonation of the peptide molecules.

scholarly journals Geometry induced sequence of nanoscale Frank–Kasper and quasicrystal mesophases in giant surfactants

2016 ◽  
Vol 113 (50) ◽  
pp. 14195-14200 ◽  
Author(s):  
Kan Yue ◽  
Mingjun Huang ◽  
Ryan L. Marson ◽  
Jinlin He ◽  
Jiahao Huang ◽  
...  
Keyword(s):  
Self Assembly ◽  
Brownian Dynamics ◽  
Molecular Model ◽  
Critical Role ◽  
Sphere Packing ◽  
Molecular Geometry ◽  
Soft Materials ◽  
Real Space ◽  
Molecular Architecture ◽  
Self Assembled

Frank–Kasper (F-K) and quasicrystal phases were originally identified in metal alloys and only sporadically reported in soft materials. These unconventional sphere-packing schemes open up possibilities to design materials with different properties. The challenge in soft materials is how to correlate complex phases built from spheres with the tunable parameters of chemical composition and molecular architecture. Here, we report a complete sequence of various highly ordered mesophases by the self-assembly of specifically designed and synthesized giant surfactants, which are conjugates of hydrophilic polyhedral oligomeric silsesquioxane cages tethered with hydrophobic polystyrene tails. We show that the occurrence of these mesophases results from nanophase separation between the heads and tails and thus is critically dependent on molecular geometry. Variations in molecular geometry achieved by changing the number of tails from one to four not only shift compositional phase boundaries but also stabilize F-K and quasicrystal phases in regions where simple phases of spheroidal micelles are typically observed. These complex self-assembled nanostructures have been identified by combining X-ray scattering techniques and real-space electron microscopy images. Brownian dynamics simulations based on a simplified molecular model confirm the architecture-induced sequence of phases. Our results demonstrate the critical role of molecular architecture in dictating the formation of supramolecular crystals with “soft” spheroidal motifs and provide guidelines to the design of unconventional self-assembled nanostructures.

scholarly journals Effect of Surface Roughness on Aggregation of Polypeptide Chains: A Monte Carlo Study

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 596
Author(s):  
Nguyen Truong Co ◽  
Mai Suan Li
Keyword(s):  
Surface Roughness ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Monte Carlo Study ◽  
The Self ◽  
Living Organisms ◽  
Polypeptide Chains ◽  
The Impact ◽  
Kinetics Of

The self-assembly of amyloidogenic peptides and proteins into fibrillar structures has been intensively studied for several decades, because it seems to be associated with a number of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Therefore, understanding the molecular mechanisms of this phenomenon is important for identifying an effective therapy for the corresponding diseases. Protein aggregation in living organisms very often takes place on surfaces like membranes and the impact of a surface on this process depends not only on the surface chemistry but also on its topology. Our goal was to develop a simple lattice model for studying the role of surface roughness in the aggregation kinetics of polypeptide chains and the morphology of aggregates. We showed that, consistent with the experiment, an increase in roughness slows down the fibril formation, and this process becomes inhibited at a very highly level of roughness. We predicted a subtle catalytic effect that a slightly rough surface promotes the self-assembly of polypeptide chains but does not delay it. This effect occurs when the interaction between the surface and polypeptide chains is moderate and can be explained by taking into account the competition between energy and entropy factors.

scholarly journals Construction of a TF–miRNA–gene feed-forward loop network predicts biomarkers and potential drugs for myasthenia gravis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunrui Bo ◽  
Huixue Zhang ◽  
Yuze Cao ◽  
Xiaoyu Lu ◽  
Cong Zhang ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mirna Gene ◽  
Experimental Studies ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Disease Genes ◽  
Feed Forward ◽  
Tf Gene

AbstractMyasthenia gravis (MG) is an autoimmune disease and the most common type of neuromuscular disease. Genes and miRNAs associated with MG have been widely studied; however, the molecular mechanisms of transcription factors (TFs) and the relationship among them remain unclear. A TF–miRNA–gene network (TMGN) of MG was constructed by extracting six regulatory pairs (TF–miRNA, miRNA–gene, TF–gene, miRNA–TF, gene–gene and miRNA–miRNA). Then, 3/4/5-node regulatory motifs were detected in the TMGN. Then, the motifs with the highest Z-score, occurring as 3/4/5-node composite feed-forward loops (FFLs), were selected as statistically significant motifs. By merging these motifs together, we constructed a 3/4/5-node composite FFL motif-specific subnetwork (CFMSN). Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MG. In addition, the genes, TFs and miRNAs in the CFMSN were also utilized to identify potential drugs. Five related genes, 3 TFs and 13 miRNAs, were extracted from the CFMSN. As the most important TF in the CFMSN, MYC was inferred to play a critical role in MG. Pathway enrichment analysis showed that the genes and miRNAs in the CFMSN were mainly enriched in pathways related to cancer and infections. Furthermore, 21 drugs were identified through the CFMSN, of which estradiol, estramustine, raloxifene and tamoxifen have the potential to be novel drugs to treat MG. The present study provides MG-related TFs by constructing the CFMSN for further experimental studies and provides a novel perspective for new biomarkers and potential drugs for MG.

scholarly journals In silicobacteria evolve robust cooperation via complex quorum-sensing strategies

2019 ◽  
Author(s):  
Yifei Wang ◽  
Jennifer B. Rattray ◽  
Stephen A. Thomas ◽  
James Gurney ◽  
Sam P. Brown
Keyword(s):  
Quorum Sensing ◽  
Experimental Evolution ◽  
Molecular Mechanisms ◽  
Bacterial Species ◽  
Critical Role ◽  
Experimental Studies ◽  
Environmental Drivers ◽  
High Signal ◽  
Environmental Challenges ◽  
Digital Organisms

AbstractMany species of bacteria collectively sense and respond to their social and physical environment via ‘quorum sensing’ (QS), a communication system controlling extracellular cooperative traits. Despite detailed understanding of the mechanisms of signal production and response, there remains considerable debate over the functional role(s) of QS: in short, what is it for? Experimental studies have found support for diverse functional roles: density sensing, mass-transfer sensing, genotype sensing, etc. While consistent with theory, these results cannot separate whether these functions were drivers of QS adaption, or simply artifacts or ‘spandrels’ of systems shaped by distinct ecological pressures. The challenge of separating spandrels from drivers of adaptation is particularly hard to address using extant bacterial species with poorly understood current ecologies (let alone their ecological histories). To understand the relationship between environmental challenges and trajectories of QS evolution, we used an agent-based simulation modeling approach. Given genetic mixing, our simulations produce behaviors that recapitulate features of diverse microbial QS systems, including coercive (high signal / low response) and generalized reciprocity (signal auto-regulation) strategists — that separately and in combination contribute to QS-dependent resilience of QS-controlled cooperation in the face of diverse cheats. We contrast ourin silicoresults with bacterial QS architectures that have evolved under largely unknown ecological contexts, highlighting the critical role of genetic constraints in shaping the shorter term (experimental evolution) dynamics of QS. More broadly, we see experimental evolution of digital organisms as a complementary tool in the search to understand the emergence of complex QS architectures and functions.Author summaryBacteria communicate and cooperate using complex cell-cell signaling systems known as quorum-sensing (QS). While the molecular mechanisms are often well understood, the reasons why bacteria use QS are less clear — how has QS aided survival and growth? The answer to this question is dependent on the environment of adaptation, and unfortunately our current understanding of QS bacterial ecology is broadly lacking. To address this gap, we studied the evolution of ‘digital organisms’, individual-based computer simulations of bacterial populations evolving under defined environmental contexts. Our results pinpoint how simple environmental challenges (variable density and genetic mixing) can lead to the emergence of complex strategies that recapitulate features of bacterial QS, and open a path towards reverse-engineering the environmental drivers of QS.

scholarly journals Dissecting the self-assembly kinetics of multimeric pore-forming toxins

2016 ◽  
Vol 13 (114) ◽  
pp. 20150762 ◽  
Author(s):  
A. A. Lee ◽  
M. J. Senior ◽  
M. I. Wallace ◽  
T. E. Woolley ◽  
I. M. Griffiths
Keyword(s):  
Single Molecule ◽  
Self Assembly ◽  
Quantitative Agreement ◽  
Time Resolved ◽  
Biologically Relevant ◽  
Low Concentrations ◽  
Assembly Kinetics ◽  
Quantitative Understanding ◽  
Mechanism And Kinetics ◽  
Kinetics Of

Pore-forming toxins are ubiquitous cytotoxins that are exploited by both bacteria and the immune response of eukaryotes. These toxins kill cells by assembling large multimeric pores on the cell membrane. However, a quantitative understanding of the mechanism and kinetics of this self-assembly process is lacking. We propose an analytically solvable kinetic model for stepwise, reversible oligomerization. In biologically relevant limits, we obtain simple algebraic expressions for the rate of pore formation, as well as for the concentration of pores as a function of time. Quantitative agreement is obtained between our model and time-resolved kinetic experiments of Bacillus thuringiensis Cry1Ac (tetrameric pore), aerolysin, Staphylococcus aureus α -haemolysin (heptameric pores) and Escherichia coli cytolysin A (dodecameric pore). Furthermore, our model explains how rapid self-assembly can take place with low concentrations of oligomeric intermediates, as observed in recent single-molecule fluorescence experiments of α-haemolysin self-assembly. We propose that suppressing the concentration of oligomeric intermediates may be the key to reliable, error-free, self-assembly of pores.

scholarly journals The vascular smooth muscle cell: a therapeutic target in Type 2 diabetes?

2013 ◽  
Vol 125 (4) ◽  
pp. 167-182 ◽  
Author(s):  
Karen E. Porter ◽  
Kirsten Riches
Keyword(s):  
Type 2 Diabetes ◽  
Smooth Muscle ◽  
Cardiovascular Risk ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Experimental Studies ◽  
Metabolic Memory ◽  
Diabetic Patients ◽  
Metabolic Disturbances

The rising epidemic of T2DM (Type 2 diabetes mellitus) worldwide is of significant concern. The inherently silent nature of the disease in its early stages precludes early detection; hence cardiovascular disease is often established by the time diabetes is diagnosed. This increased cardiovascular risk leads to significant morbidity and mortality in these individuals. Progressive development of complications as a result of previous exposure to metabolic disturbances appears to leave a long-lasting impression on cells of the vasculature that is not easily reversed and is termed ‘metabolic memory’. SMCs (smooth muscle cells) of blood vessel walls, through their inherent ability to switch between a contractile quiescent phenotype and an active secretory state, maintain vascular homoeostasis in health and development. This plasticity also confers SMCs with the essential capacity to adapt and remodel in pathological states. Emerging clinical and experimental studies propose that SMCs in diabetes may be functionally impaired and thus contribute to the increased incidence of macrovascular complications. Although this idea has general support, the underlying molecular mechanisms are currently unknown and hence are the subject of intense research. The aim of the present review is to explore and evaluate the current literature relating to the problem of vascular disease in T2DM and to discuss the critical role of SMCs in vascular remodelling. Possibilities for therapeutic strategies specifically at the level of T2DM SMCs, including recent novel advances in the areas of microRNAs and epigenetics, will be evaluated. Since restoring glucose control in diabetic patients has limited effect in ameliorating their cardiovascular risk, discovering alternative strategies that restrict or reverse disease progression is vital. Current research in this area will be discussed.

Insights Into the Molecular Mechanisms of Actin Dynamics: A Multiscale Modeling Approach

2011 ◽  
Author(s):  
Tamara C. Bidone ◽  
Marco A. Deriu ◽  
Giacomo Di Benedetto ◽  
Diana Massai ◽  
Umberto Morbiducci
Keyword(s):  
Cell Migration ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Multiple Equilibrium ◽  
Actin Dynamics ◽  
Cellular Processes ◽  
Kinetics Of ◽  
Binding Loop ◽  
Conformational Shifts

Actin dynamics, which is at the basis of many fundamental cellular processes as cell migration [1], is governed by the self-assembly and disassembly of actin monomers (G-actin) that, in turn, are determined by the kinetics of ATP hydrolysis and by the local concentrations of Mg2+ and Ca2+ [2]. During cell migration, interactions of the actin filaments (F-actin) with different nucleotide-cation complexes induce local topological rearrangements, because the filament building G-actins undergo conformational shifts between multiple equilibrium states separated by low-energy barriers. For example, the structural rearrangements of the DNase-I binding loop (residues 38–52) in subdomain 2 are driven by ATP hydrolysis and the changes in the conformation of subdomain 4 are induced by the presence of a tightly-bound Mg2+ or Ca2+ ion (Figure 1a). These conformational shifts alter the cross-linking between monomers, varying the contact surfaces among adjacent inter- and intrasubdomains of G-actin, and reflect on the overall properties of F-actin.

Structural Studies of Fibrinolysis by Electron and Light Microscopy

1999 ◽  
Vol 82 (08) ◽  
pp. 277-282 ◽  
Author(s):  
Yuri Veklich ◽  
Jean-Philippe Collet ◽  
Charles Francis ◽  
John W. Weisel
Keyword(s):  
Electron Microscopy ◽  
Light Microscopy ◽  
Plasminogen Activator ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Degradation Products ◽  
Molecular Model ◽  
Three Dimensional ◽  
Tissue Type ◽  
Type Plasminogen Activator

IntroductionMuch is known about the fibrinolytic system that converts fibrin-bound plasminogen to the active protease, plasmin, using plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plasmin then cleaves fibrin at specific sites and generates soluble fragments, many of which have been characterized, providing the basis for a molecular model of the polypeptide chain degradation.1-3 Soluble degradation products of fibrin have also been characterized by transmission electron microscopy, yielding a model for their structure.4 Moreover, high resolution, three-dimensional structures of certain fibrinogen fragments has provided a wealth of information that may be useful in understanding how various proteins bind to fibrin and the overall process of fibrinolysis (Doolittle, this volume).5,6 Both the rate of fibrinolysis and the structures of soluble derivatives are determined in part by the fibrin network structure itself. Furthermore, the activation of plasminogen by t-PA is accelerated by the conversion of fibrinogen to fibrin, and this reaction is also affected by the structure of the fibrin. For example, clots made of thin fibers have a decreased rate of conversion of plasminogen to plasmin by t-PA, and they generally are lysed more slowly than clots composed of thick fibers.7-9 Under other conditions, however, clots made of thin fibers may be lysed more rapidly.10 In addition, fibrin clots composed of abnormally thin fibers formed from certain dysfibrinogens display decreased plasminogen binding and a lower rate of fibrinolysis.11-13 Therefore, our increasing knowledge of various dysfibrinogenemias will aid our understanding of mechanisms of fibrinolysis (Matsuda, this volume).14,15 To account for these diverse observations and more fully understand the molecular basis of fibrinolysis, more knowledge of the physical changes in the fibrin matrix that precede solubilization is required. In this report, we summarize recent experiments utilizing transmission and scanning electron microscopy and confocal light microscopy to provide information about the structural changes occurring in polymerized fibrin during fibrinolysis. Many of the results of these experiments were unexpected and suggest some aspects of potential molecular mechanisms of fibrinolysis, which will also be described here.

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