An Equilibrium Model for the Combined Effect of Macromolecular Crowding and Surface Adsorption on the Formation of Linear Protein Fibrils

Hoppe, Travis; Minton, Allen P.

doi:10.1016/j.bpj.2014.12.033

Cited by 21 publications

(14 citation statements)

References 37 publications

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“…For example, the positional variability of folding kinetics and equilibrium of a mutant of phosphoglycerokinase fused to green and red fluorescent proteins in intact U2OS (mammalian) cells is clearly non-random (Figures 3A,B), and appears to correlate with supramolecular structures such as membranes or cytoskeletal fibers within the cell 55 . This could indicate that the in-cell behavior of a probe molecule may be influenced by its interaction with surfaces as much as by crowding in the bulk medium, as has been suggested previously 6, 8, 66, 67 .…”

Section: What Have We Learned From “In Vivo” Experiments?supporting

confidence: 53%

Macromolecular Crowding In Vitro , In Vivo , and In Between

Rivas

Minton

2016

Trends in Biochemical Sciences

405

370

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Biochemical processes take place in heterogeneous and highly volume occupied or crowded environments that can considerably influence the reactivity and distribution of participating macromolecules. Here we summarize the thermodynamic consequences of excluded volume and longer-ranged nonspecific intermolecular interactions for macromolecular reactions in volume-occupied media. In addition, we summarize and compare the information content of studies of crowding in vitro and in vivo. We emphasize the importance of characterizing the behavior not only of labeled tracer macromolecules, but also the composition and behavior of unlabeled macromolecules in the immediate vicinity of the tracer. Finally, we propose strategies for extending quantitative analyses of crowding in simple model systems to increasingly complex media up to and including intact cells.

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Section: What Have We Learned From “In Vivo” Experiments?supporting

confidence: 53%

Macromolecular Crowding In Vitro , In Vivo , and In Between

Rivas

Minton

2016

Trends in Biochemical Sciences

405

370

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“…1D, 2C, 3C and 4B). Upon increasing the crowding agent concentration up to 300-400 mg/ml, however, no change in amyloid aggregation mechanisms with a short lag phase was observed (not shown), unlike in the presence of alcohols or salts, probably because of the well-documented enhancement of surfacecatalyzed protein fibril formation in the presence of macromolecular crowders 42 .…”

Section: Addition Of Macromolecular Crowders Also Accelerates αS Nuclmentioning

confidence: 94%

The extent of protein hydration dictates the preference for heterogeneous or homogeneous nucleation generating either parallel or antiparallel β-sheet α-synuclein aggregates

Camino

Gracia

Chen

et al. 2020

Preprint

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α-Synuclein amyloid self-assembly is the hallmark of a number of neurodegenerative disorders, including Parkinson’s disease, although there is still very limited understanding about the factors and mechanisms that trigger this process. Primary nucleation has been observed to be initiated in vitro at hydrophobic/hydrophilic interfaces by heterogeneous nucleation generating parallel β-sheet aggregates, although no such interfaces have yet been identified in vivo. In this work, we have discovered that α-synuclein can self-assemble into amyloid aggregates by homogeneous nucleation, without the need of an active surface, and with a preference for an antiparallel β-sheet arrangement. This particular structure has been previously proposed to be distinctive of stable toxic oligomers and we here demonstrate that it indeed represents the most stable structure of the preferred amyloid pathway triggered by homogeneous nucleation under limited hydration conditions, including those encountered inside α-synuclein droplets generated by liquid-liquid phase separation. In addition, our results highlight the key role that water plays not only in modulating the transition free energy of amyloid nucleation, and thus governing the initiation of the process, but also in dictating the type of preferred primary nucleation and the type of amyloid polymorph generated depending on the extent of protein hydration. These findings are particularly relevant in the context of in vivo α-synuclein aggregation where the protein can encounter a variety of hydration conditions in different cellular microenvironments, including the vicinity of lipid membranes or the interior of membraneless compartments, which could lead to the formation of remarkably different amyloid polymorphs by either heterogeneous or homogeneous nucleation.

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“…Recent investigations probing the effects of crowding on protein aggregation have mainly focused on using molecular simulation to explicitly sample the interactions between proteins and crowders in 3D, [40][41][42] and on using kinetic massaction kinetics models for computing the changes to the cluster size distributions as a function of time. 23,35,36,[43][44][45] For example, Magno et al 40 used a simplified Lennard-Jones potential to quantify the interactions between the proteins and the crowders, and Langevin dynamics simulations to sample aggregation trajectories. They found that the crowders stabilized oligomers, and increased the solution viscosity.…”

Section: Previous Studies Of the Effects Of Molecular Crowding Onmentioning

confidence: 99%

Investigating the effects of molecular crowding on the kinetics of protein aggregation

Schreck

Bridstrup

Yuan

2020

Preprint

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The thermodynamics and kinetics of protein folding and protein aggregation in vivo are of great importance in numerous scientific areas including fundamental biophysics research, nanotechnology, and medicine. However, these processes remain poorly understood in both in vivo and in vitro systems. Here we extend an established model for protein aggregation that is based on the kinetic equations for the moments of the polymer size distribution by introducing macromolecular crowding particles into the model using scaled-particle and transition-state theories. The model predicts that the presence of crowders can either speed up, cause no change to, or slow down the progress of the aggregation compared to crowder-free solutions, in striking agreement with experimental results from nine different amyloid-forming proteins that utilized dextran as the crowder. These different dynamic effects of macromolecular crowding can be understood in terms of the change of excluded volume associated with each reaction step.

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An Equilibrium Model for the Combined Effect of Macromolecular Crowding and Surface Adsorption on the Formation of Linear Protein Fibrils

Cited by 21 publications

References 37 publications

Macromolecular Crowding In Vitro , In Vivo , and In Between

Macromolecular Crowding In Vitro , In Vivo , and In Between

The extent of protein hydration dictates the preference for heterogeneous or homogeneous nucleation generating either parallel or antiparallel β-sheet α-synuclein aggregates

Investigating the effects of molecular crowding on the kinetics of protein aggregation

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