Highly Charged Proteins: The Achilles' Heel of Aging Proteomes

Graff, Adam M.R. de; Hazoglou, Michael; Dill, Ken A.

doi:10.1016/j.str.2015.11.006

Cited by 61 publications

(73 citation statements)

References 56 publications

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“…Aspects of charge‐directed behavior of biomacromolecules on for example polyelectrolyte effects, ionic strength‐mediated charge screening, and salt bridge formation have been reviewed extensively and will hence not be discussed here . As summarized in Figure , we will first highlight naturally occurring supercharged proteins, folded and unstructured ones.…”

Section: Introductionmentioning

confidence: 99%

Supercharged Proteins and Polypeptides

Malessa

Boersma

et al. 2020

Advanced Materials

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Electrostatic interactions play a vital role in nature. Biomacromolecules such as proteins are orchestrated by electrostatics, among other intermolecular forces, to assemble and organize biochemistry. Natural proteins with a high net charge exist in a folded state or are unstructured and can be an inspiration for scientists to artificially supercharge other protein entities. Recent findings show that supercharging proteins allows for control of their properties such as temperature resistance and catalytic activity. One elegant method to transfer the favorable properties of supercharged proteins to other proteins is the fabrication of fusions. Genetically engineered, supercharged unstructured polypeptides (SUPs) are just one promising fusion tool. SUPs can also be complexed with artificial entities to yield thermotropic and lyotropic liquid crystals and liquids. These architectures represent novel bulk materials that are sensitive to external stimuli. Interestingly, SUPs undergo fluid–fluid phase separation to form coacervates. These coacervates can even be directly generated in living cells or can be combined with dissipative fiber assemblies that induce life‐like features. Supercharged proteins and SUPs are developed into exciting classes of materials. Their synthesis, structures, and properties are summarized. Moreover, potential applications are highlighted and challenges are discussed.

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Section: Introductionmentioning

confidence: 99%

Supercharged Proteins and Polypeptides

Malessa

Boersma

et al. 2020

Advanced Materials

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“…Misfolded intermediates can dominate folding pathways (4)(5)(6)(7), drive evolution of the coding sequence (8)(9)(10), and cause proteins to assemble into aggregates linked to common diseases (11)(12)(13)(14)(15)(16)(17). Post-translational modifications often affect the relative stabilities of intermediates within the conformational ensemble (18)(19)(20)(21)(22)(23)(24). Where a protein is present at a high concentration, the question arises: Can distinct intermediate states interact or affect one another in a functionally significant way?…”

Section: Introductionmentioning

confidence: 99%

Conformational catalysis of cataract-associated aggregation in a human eye lens crystallin occurs via interface stealing

Serebryany

et al. 2019

Preprint

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Human γD-crystallin (HγD) is an abundant and highly stable two-domain protein in the core region of the eye lens. Destabilizing mutations and post-translational modifications in this protein are linked to onset of aggregation that causes cataract disease (lens turbidity). Wild-type HγD greatly accelerates aggregation of the cataract-related W42Q variant, without itself aggregating. The mechanism of this "inverse prion" catalysis of aggregation remained unknown. Here we provide evidence that an early unfolding intermediate with an opened domain interface enables transient dimerization of the C-terminal domains of wildtype and mutant, or mutant and mutant, HγD molecules, which deprives the mutant's Nterminal domain of intramolecular stabilization by the native domain interface and thus accelerates its misfolding to a distinct, aggregation-prone intermediate. A detailed kinetic model predicts universal power-law scaling relationships for lag time and rate of the resulting aggregation, which are in excellent agreement with the data. The mechanism reported here, which we term interface stealing, can be generalized to explain how common domain-domain interactions can have surprising consequences, such as conformational catalysis of unfolding, in multidomain proteins. SignificanceMost known proteins in nature consist of multiple domains. Interactions between domains may lead to unexpected folding and misfolding phenomena. This study of human γD-crystallin, a two-domain protein in the eye lens, revealed one such surprise: conformational catalysis of misfolding via intermolecular domain interface "stealing." An intermolecular interface between the more stable domains outcompetes the native intramolecular domain interface. Loss of the native interface in turn promotes misfolding and subsequent aggregation, especially in cataractrelated γD-crystallin variants. This phenomenon is likely a contributing factor in the development of cataract disease, the leading worldwide cause of blindness. However, interface stealing likely occurs in many proteins composed of two or more interacting domains.

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“…related to translation have previously been observed to be significantly enriched in aggregate inclusions of older worms compared with younger ones, and to modulate the lifespan of the organism on RNAi knock-down (37). Proteins belonging to this functional class have also been predicted to be at the highest risk for oxidative damage, which is a dominant source of the loss of protein stability and solubility on aging (66). On oxidative stress, several proteins decrease their solubility because of oxidation.…”

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confidence: 99%

Proteome-wide observation of the phenomenon of life on the edge of solubility

Vecchi

Sormanni

Mannini

et al. 2019

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

131

119

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To function effectively proteins must avoid aberrant aggregation, and hence they are expected to be expressed at concentrations safely below their solubility limits. By analyzing proteome-wide mass spectrometry data of Caenorhabditis elegans, however, we show that the levels of about three-quarters of the nearly 4,000 proteins analyzed in adult animals are close to their intrinsic solubility limits, indeed exceeding them by about 10% on average. We next asked how aging and functional self-assembly influence these solubility limits. We found that despite the fact that the total quantity of proteins within the cellular environment remains approximately constant during aging, protein aggregation sharply increases between days 6 and 12 of adulthood, after the worms have reproduced, as individual proteins lose their stoichiometric balances and the cellular machinery that maintains solubility undergoes functional decline. These findings reveal that these proteins are highly prone to undergoing concentration-dependent phase separation, which on aging is rationalized in a decrease of their effective solubilities, in particular for proteins associated with translation, growth, reproduction, and the chaperone system.

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Highly Charged Proteins: The Achilles' Heel of Aging Proteomes

Cited by 61 publications

References 56 publications

Supercharged Proteins and Polypeptides

Supercharged Proteins and Polypeptides

Conformational catalysis of cataract-associated aggregation in a human eye lens crystallin occurs via interface stealing

Proteome-wide observation of the phenomenon of life on the edge of solubility

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