Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo, Michele

doi:10.1039/b905825g

Cited by 7 publications

(5 citation statements)

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“…While a plentiful abundance of a given protein in the cell optimises its function, being on the verge of insolubility leaves proteins susceptible to environmental changes and prone to aggregation [59]. Our findings are consistent with this hypothesis [58], since elevated protein levels increase the likelihood of intermolecular as opposed to intramolecular interactions, and suggest that a precarious balance between hydrogen bonding and hydrophobic forces dictates whether peptides and proteins adopt normal or aberrant biological roles.…”

Section: Discussionsupporting

confidence: 83%

Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation

et al. 2011

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Identifying the forces that drive proteins to misfold and aggregate, rather than to fold into their functional states, is fundamental to our understanding of living systems and to our ability to combat protein deposition disorders such as Alzheimer's disease and the spongiform encephalopathies. We report here the finding that the balance between hydrophobic and hydrogen bonding interactions is different for proteins in the processes of folding to their native states and misfolding to the alternative amyloid structures. We find that the minima of the protein free energy landscape for folding and misfolding tend to be respectively dominated by hydrophobic and by hydrogen bonding interactions. These results characterise the nature of the interactions that determine the competition between folding and misfolding of proteins by revealing that the stability of native proteins is primarily determined by hydrophobic interactions between side-chains, while the stability of amyloid fibrils depends more on backbone intermolecular hydrogen bonding interactions.

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Section: Discussionsupporting

confidence: 83%

Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation

et al. 2011

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“…A detailed understanding of the factors allowing proteins and other macromolecules to remain soluble in their functional monomeric or multimeric states in the crowded environment of the cell is of central importance in biology (25,26). The dynamic properties of proteins can play key roles in influencing their propensity for self-ssembly and aggregation (14) and have considerable significance in many aspects of their function (27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Intrinsic disorder modulates protein self-assembly and aggregation

Simone

Kitchen

Kwan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Protein molecules have evolved to adopt distinctive and welldefined functional and soluble states under physiological conditions. In some circumstances, however, proteins can self-assemble into fibrillar aggregates designated as amyloid fibrils. In vivo these processes are normally associated with severe pathological conditions but can sometimes have functional relevance. One such example is the hydrophobins, whose aggregation at air-water interfaces serves to create robust protein coats that help fungal spores to resist wetting and thus facilitate their dispersal in the air. We have performed multiscale simulations to address the molecular determinants governing the formation of functional amyloids by the class I fungal hydrophobin EAS. Extensive samplings of full-atom replica-exchange molecular dynamics and coarse-grained simulations have allowed us to identify factors that distinguish aggregation-prone from highly soluble states of EAS. As a result of unfavourable entropic terms, highly dynamical regions are shown to exert a crucial influence on the propensity of the protein to aggregate under different conditions. More generally, our findings suggest a key role that specific flexible structural elements can play to ensure the existence of soluble and functional states of proteins under physiological conditions. amyloid formation | protein aggregation | protein dynamics T he identification of the factors that enable proteins and macromolecules to remain functional and soluble under physiological conditions is of central importance in biology (1). The ability to avoid inappropriate protein aggregation is a distinctive property of all functional biological macromolecules and assumes a particularly crucial role in disfavoring aberrant processes such as those involving protein self-assembly into highly organized amyloid fibrils; these latter processes are associated with a range of severe pathological conditions, including neurodegenerative disorders such as Alzheimer's and Parkinson diseases and a number of nonneuropathic conditions including type II diabetes (2-4). In vivo, amyloid formation is largely pathogenic, although in some cases it can have functional relevance, as for example in the storage of peptide hormones in mammals (5) or the response to nutrient depletion conditions in yeast (6). It has become apparent, however, that the ability to form amyloid structures is a common characteristic of polypeptide chains in vitro (7); this finding begs the question of how the majority of the peptides and proteins in a living system are able to suppress such processes under normal circumstances.It is well established that there are multiple strategies within biological organisms to inhibit aberrant protein aggregation, including the regulation of protein expression levels (8) and the existence of quality control mechanisms to detect and degrade misfolded conformations (9-12). The principal means for controlling misfolding and aggregation are, however, intrinsic factors that proteins have optimized throughout evolu...

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“…irtually every complex biochemical process taking place in living cells depends on the ability of the molecules involved to selfassemble into functional structures (Dobson 2003;Robinson et al 2007;Russel et al 2009), and a sophisticated quality control system is responsible for regulating the reactions leading to this organization within the cellular environment (Dobson 2003;Balch et al 2008;Hartl and Hayer-Hartl 2009;Powers et al 2009;Vendruscolo and Dobson 2009). Proteins are the molecules that are essential for enabling, regulating, and controlling almost all the tasks necessary to maintain such a balance.…”

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confidence: 99%

Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders

Vendruscolo¹,

Knowles²,

Dobson³

2011

Cold Spring Harbor Perspectives in Biology

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According to the "generic view" of protein aggregation, the ability to self-assemble into stable and highly organized structures such as amyloid fibrils is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but rather a property shared by most proteins. At the same time, through a wide variety of techniques, many of which were originally devised for applications in other disciplines, it has also been established that the maintenance of proteins in a soluble state is a fundamental aspect of protein homeostasis. Taken together, these advances offer a unified framework for understanding the molecular basis of protein aggregation and for the rational development of therapeutic strategies based on the biological and chemical regulation of protein solubility.

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Quantitative approaches to defining normal and aberrant protein homeostasis

Cited by 7 publications

References 78 publications

Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation

Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation

Intrinsic disorder modulates protein self-assembly and aggregation

Protein Solubility and Protein Homeostasis: A Generic View of Protein Misfolding Disorders

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