Protein Aggregation and Disaggregation in Cells and Development

Fassler, Jan S.; Skuodas, Sydney; Weeks, Daniel L.; Phillips, Bryan T.

doi:10.1016/j.jmb.2021.167215

Cited by 28 publications

(20 citation statements)

References 175 publications

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“…Indeed, it has been shown that ectopic expression of HSP104 (yeast disaggregase) in C. elegans caused cell division defects and embryonic lethality (Skuodas et al 2020). These findings suggest that amyloid aggregates and/or biological condensates are a normal aspect of physiological functions and that their proper regulation is essential (Fassler et al 2021). During aging the germline stem cells are reported to be quiescent, mitotic and meiotic processes comes to a halt and the proteins might not be properly distributed to the daughter cells.…”

Section: Discussionmentioning

confidence: 99%

“…Protein aggregates are considered inherently irreversible aberrant clumps, and are often associated with pathologies (Hipp et al 2014; Soto and Pritzkow, 2018). However, recent evidence demonstrates that protein aggregation can also be an active, organized process (Fassler et al 2021; Miller at al., 2015; Boronat et al 2021). Physiological and reversible protein aggregation which seem to be beneficial has been observed in diverse systems from yeast to mammalian cells (Wallace et al 2015; Saad et al 2017; Becker and Gitler 2018; Cereghetti et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Regulated and often reversible formation of protein aggregates or condensates perform a wide variety of cellular functions including response to stress, gene expression, cellular development and differentiation etc. (Alberti and Hyman., 2021; Fassler et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Extent of Molecular Chaperone Association Might Determine Fates of Membraneless Organelles during Aging in C. elegans

Mukherjee

Panda

Kasturi

2021

Preprint

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Proteome imbalance can lead to protein misfolding and aggregation which is associated with pathologies. Protein aggregation can also be an active, organized process and can be exploited by cells as a survival strategy. In adverse conditions, it is beneficial to deposit the proteins in a condensate rather degrading and resynthesizing. Membrane less organelles (MLOs) are biological condensates formed through liquid liquid phase separation (LLPS), involving cellular components such as nucleic acids and proteins. LLPS is a regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates. To understand how the MLO-associated proteins (MLO-APs) behave during aging, we performed a comparative meta analysis with age related proteome of C. elegans. We found that the MLO-APs are highly abundant throughout the lifespan. Interestingly, they are aggregating more in long-lived mutant worms compared to the age matched wildtype worms. GO term analysis revealed that the cell cycle and embryonic development are among the top enriched processes in addition to RNA metabolism RNP components. Considering antagonistic pleotropic nature of these developmental genes and post mitotic status of C. elegans, we assume that these proteins phase transit during post development. As the organism ages, these MLO-APs either mature to become more insoluble or dissolve in uncontrolled manner. However, in the long-lived daf-2 mutant worms, the MLOs may attain protective states due to enhanced proteostasis components and altered metabolism that eventually make these worms more protected.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extent of Molecular Chaperone Association Might Determine Fates of Membraneless Organelles during Aging in C. elegans

Mukherjee

Panda

Kasturi

2021

Preprint

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“…As discussed above, dramatic improvement in atomistic protein force fields coupled with enhanced samplings and GPU computing have now enabled us to generate the disordered conformational ensembles of increasingly complex IDPs in both bound and unbound states. Many important phenomena related to IDPs remain largely out of the reach of physics-based atomistic simulations, such as aggregation [132][133][134] and biological condensates [135][136][137][138]. Here, we review two of the key multi-scale approaches that allow one to simulate longer time-scale bioprocesses and more complex systems within the capacity of current computational capability, namely implicit solvent and coarse-grained (CG) models.…”

Section: Multi-scale Approaches For Overcoming Sampling Problems Of Large Systemsmentioning

confidence: 99%

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

Gong

Chen

2021

Biomolecules

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Intrinsically disordered proteins (IDPs) are highly prevalent and play important roles in biology and human diseases. It is now also recognized that many IDPs remain dynamic even in specific complexes and functional assemblies. Computer simulations are essential for deriving a molecular description of the disordered protein ensembles and dynamic interactions for a mechanistic understanding of IDPs in biology, diseases, and therapeutics. Here, we provide an in-depth review of recent advances in the multi-scale simulation of disordered protein states, with a particular emphasis on the development and application of advanced sampling techniques for studying IDPs. These techniques are critical for adequate sampling of the manifold functionally relevant conformational spaces of IDPs. Together with dramatically improved protein force fields, these advanced simulation approaches have achieved substantial success and demonstrated significant promise towards the quantitative and predictive modeling of IDPs and their dynamic interactions. We will also discuss important challenges remaining in the atomistic simulation of larger systems and how various coarse-grained approaches may help to bridge the remaining gaps in the accessible time- and length-scales of IDP simulations.

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“…While proteostatic networks can be organized in a variety of ways, the core components are conserved across phylogeny, including several families of essential molecular chaperones ( Rosenzweig et al, 2019 ; Balchin et al, 2020 ). Importantly, while molecular chaperones are generally required for facilitating protein folding and preventing aggregation, molecular chaperones are also necessary for recognizing and dismantling protein aggregates ( Mogk et al, 2018 ; Fassler et al, 2021 ). The Hsp70 class of molecular chaperones and some of their associated cofactors (the Hsp40 targeting factors and nucleotide exchange factors or NEFs), play a central role in the response to aggregate formation in virtually all organisms ( Mogk et al, 2018 ; Mayer and Gierasch, 2019 ; Kohler and Andréasson, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones

Shoup

Roth

Puchalla

et al. 2022

Front. Mol. Biosci.

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Protein aggregation, or the uncontrolled self-assembly of partially folded proteins, is an ever-present danger for living organisms. Unimpeded, protein aggregation can result in severe cellular dysfunction and disease. A group of proteins known as molecular chaperones is responsible for dismantling protein aggregates. However, how protein aggregates are recognized and disassembled remains poorly understood. Here we employ a single particle fluorescence technique known as Burst Analysis Spectroscopy (BAS), in combination with two structurally distinct aggregate types grown from the same starting protein, to examine the mechanism of chaperone-mediated protein disaggregation. Using the core bi-chaperone disaggregase system from Escherichia coli as a model, we demonstrate that, in contrast to prevailing models, the overall size of an aggregate particle has, at most, a minor influence on the progression of aggregate disassembly. Rather, we show that changes in internal structure, which have no observable impact on aggregate particle size or molecular chaperone binding, can dramatically limit the ability of the bi-chaperone system to take aggregates apart. In addition, these structural alterations progress with surprising speed, rendering aggregates resistant to disassembly within minutes. Thus, while protein aggregate structure is generally poorly defined and is often obscured by heterogeneous and complex particle distributions, it can have a determinative impact on the ability of cellular quality control systems to process protein aggregates.

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Protein Aggregation and Disaggregation in Cells and Development

Cited by 28 publications

References 175 publications

Extent of Molecular Chaperone Association Might Determine Fates of Membraneless Organelles during Aging in C. elegans

Extent of Molecular Chaperone Association Might Determine Fates of Membraneless Organelles during Aging in C. elegans

Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

The Impact of Hidden Structure on Aggregate Disassembly by Molecular Chaperones

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