Protein Fibrillation under Crowded Conditions

Gorensek-Benitez, Annelise H.; Kirk, Bryan; Myers, Jeffrey K.

doi:10.3390/biom12070950

Cited by 5 publications

(3 citation statements)

References 108 publications

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“…Specifically, condensed biomolecules, such as membraneless organelles, are prone to contain nonspecific protein species and to mis‐sequester proteins as a result of modifications of the primary structure of a protein elicited by either genetic alterations, environmental insults, or both, such as non‐synonymous mutations or insult‐elicited post‐translational modifications [14,19,27,31–37]. These protein changes can drive aberrant LLPS or liquid‐to‐solid phase transitions of biomolecular condensates (e.g., changes in threshold of percolation) that affect biophysical and structural properties of assembly and disassembly of protein ensembles, and ultimately, protein homeostasis (aka, proteostasis).…”

Section: Phase Transitions In Neurodegenerationmentioning

confidence: 99%

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

Ferreira

2023

FEBS Letters

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Nucleocytoplasmic transport comprises the multistep assembly, transport and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits – another hallmark of neurodegeneration. Disturbances in liquid–liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer‐scale coacervates, leading to proteinaceous aggregates. This Review provides historical and emerging principles of LLPS at the interface of nucleocytoplasmic transport, proteostasis, aging and noxious insults, whose dysregulations promote intracellular aggregates. E3 SUMO‐protein ligase Ranbp2 constitutes the cytoplasmic filaments of nuclear pores, where it acts as a molecular hub for rate‐limiting steps of nucleocytoplasmic transport. A vignette is provided on the roles of Ranbp2 in nucleocytoplasmic transport and at the intersection of proteostasis in the survival of photoreceptor and motor neurons under homeostatic and pathophysiological environments. Current unmet clinical needs are highlighted, including therapeutics aiming to manipulate aggregation‐dissolution models of purported neurotoxicity in neurodegeneration.

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Section: Phase Transitions In Neurodegenerationmentioning

confidence: 99%

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

Ferreira

2023

FEBS Letters

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“…In contrast, under isolated conditions (in vitro), this functionality is inefficient, as the complex formation and substrate binding rely on the presence of crowding agents in solution 7 . Macromolecular crowding has also been linked to amyloidogenesis and protein fibrillation, which has tangible implications for various diseases such as Alzheimer's or Parkinson's [8][9][10] . The fibrillation process 11,12 can be accelerated or decelerated by the presence of macromolecular crowders based on a counterplay between the influence of the excluded volume and the changes in viscosity 10,13 .…”

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confidence: 99%

Bioinspired crowding directs supramolecular polymerisation

et al. 2023

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Crowding effects are crucial to maintaining functionality in biological systems, but little is known about their role in analogous artificial counterparts. Within the growing field of supramolecular polymer science, crowding effects have hitherto remained underappreciated. Herein, we show that crowding effects exhibit strong and distinct control over the kinetics, accessible pathways and final outcomes of supramolecular polymerisation processes. In the presence of a pre-formed supramolecular polymer as crowding agent, a model supramolecular polymer dramatically changes its self-assembly behaviour and undergoes a morphological transformation from bundled fibres into flower-like hierarchical assemblies, despite no co-assembly taking place. Notably, this new pathway can only be accessed in crowded environments and when the crowding agent exhibits a one-dimensional morphology. These results allow accessing diverse morphologies and properties in supramolecular polymers and pave the way towards a better understanding of high-precision self-assembly in nature.

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“…Our results suggest that formulation with PEG and other synthetic polymers may increase the performance of biological drugs not only by increasing stability but also by lowering the concentration of aggregation-prone intermediates. This effect, however, is not universal; synthetic polymers can accelerate aggregation of some globular proteins but probably via surface interactions between the crowders and the native state . Thus, the need remains to assess synthetic polymers with different surface properties.…”

mentioning

confidence: 99%

Macromolecular Crowding by Polyethylene Glycol Reduces Protein Breathing

Chu

Hutcheson

Malsch

et al. 2023

J. Phys. Chem. Lett.

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Most efforts to understand macromolecular crowding focus on global (i.e., complete) unfolding, but smaller excursions, often called breathing, promote aggregation, which is associated with several diseases and the bane of pharmaceutical and commercial protein production. We used NMR to assess the effects of ethylene glycol (EG) and polyethylene glycols (PEGs) on the structure and stability of the B1 domain of protein G (GB1). Our data show that EG and PEGs stabilize GB1 differently. EG interacts with GB1 more strongly than PEGs, but neither affects the structure of the folded state. EG and 12000 g/mol PEG stabilize GB1 more than PEGs of intermediate size, but EG and smaller PEGs stabilize GB1 enthalpically while the largest PEG acts entropically. Our key finding is that PEGs turn local unfolding into global unfolding, and meta-analysis of published data supports this conclusion. These efforts provide knowledge that can be applied to improve biological drugs and commercial enzymes.

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Protein Fibrillation under Crowded Conditions

Cited by 5 publications

References 108 publications

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

Bioinspired crowding directs supramolecular polymerisation

Macromolecular Crowding by Polyethylene Glycol Reduces Protein Breathing

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