Compacting Proteins: Pros and Cons of Osmolyte-Induced Folding

Melo, Eduardo P.; Estrela, Nídia; Lopes, Carlos; Matias, Ana Catarina; Tavares, Evandro; Ochoa-Mendes, Vanessa

doi:10.2174/138920310794557727

Cited by 13 publications

(20 citation statements)

References 77 publications

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“…However, osmolytes are capable of influencing the dynamics of structural changes of native proteins by reducing the heterogeneity of the distribution of the protein conformers in solution [84][85][86][87][88]. In turn, the introduction of osmolytes into solutions that contain denatured or partially denatured proteins results in the compaction of protein structure and decreases the diversity of its conformations [65,[89][90][91][92]. Notably, compaction of unfolded protein structure can lead to protein aggregation and improper folding.…”

Section: Protein Folding In Osmolyte Solutionsmentioning

confidence: 99%

“…Notably, compaction of unfolded protein structure can lead to protein aggregation and improper folding. However, this does not occur in osmolyte solutions [89]. Therefore, it has been proposed that osmolytes exert their effect predominantly not on denatured protein structures, but on the transition or intermediate state between the native and denatured protein conformation [93].…”

Section: Protein Folding In Osmolyte Solutionsmentioning

confidence: 99%

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Protein folding and stability in the presence of osmolytes

et al. 2016

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Osmolytes are molecules whose function, among others, is to balance the hydrostatic pressure between the intracellular and extracellular compartments. Accumulation of osmolytes in a cell occurs in response to stress caused by changes in pressure, temperature, pH, or the concentration of inorganic salts. Osmolytes can prevent the denaturation of native proteins and promote the renaturation of unfolded proteins. Investigation of the roles of osmolyte in these processes is essential for our understanding of the mechanisms of protein folding and function in vivo. The large number of published reports that have been devoted to the effects of osmolytes on proteins are not always consistent with each other. In this review, an attempt is made to systemize the array of data on this subject and to consider the problem of protein folding and stability in osmolyte solutions from a single viewpoint.

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Section: Protein Folding In Osmolyte Solutionsmentioning

confidence: 99%

Section: Protein Folding In Osmolyte Solutionsmentioning

confidence: 99%

Protein folding and stability in the presence of osmolytes

et al. 2016

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“…Glycerol and N‐ trimethylamine oxide (TMAO) were shown to decrease cytotoxicity induced by an expanded polyglutamine stretch in protein ataxin‐3 involved in Machado‐Joseph disease . The use of osmolytes as protein stabilizers and modulators of protein fibrillation is intrinsically related to the fact that osmolytes induce protein compaction to shield protein surface from the solvent, as shown recently at the single molecule level . These compounds are preferentially excluded from the protein surface, resulting in an osmolyte deficit in the vicinity, and leading to an increase in the protein chemical potential .…”

Section: Introductionmentioning

confidence: 99%

Sucrose prevents protein fibrillation through compaction of the tertiary structure but hardly affects the secondary structure

Estrela

Franquelim²,

Lopes

et al. 2015

Proteins

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Amyloid fibers, implicated in a wide range of diseases, are formed when proteins misfold and stick together in long rope-like structures. As a natural mechanism, osmolytes can be used to modulate protein aggregation pathways with no interference with other cellular functions. The osmolyte sucrose delays fibrillation of the ribosomal protein S6 leading to softer and less shaped-defined fibrils. The molecular mechanism used by sucrose to delay S6 fibrillation was studied based on the two-state unfolding kinetics of the secondary and tertiary structures. It was concluded that the delay in S6 fibrillation results from stabilization and compaction of the slightly expanded tertiary native structure formed under fibrillation conditions. Interestingly, this compaction extends to almost all S6 tertiary structure but hardly affects its secondary structure. The part of the S6 tertiary structure that suffered more compaction by sucrose is known to be the first part to unfold, indicating that the native S6 has entered the unfolding pathway under fibrillation conditions.

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“…Similarly, it is often implied that preferentially excluded cosolvents increase protein-protein interactions, whereas cosolvents that preferentially interact with the protein surface weaken protein-protein interactions. This dichotomy is, however, irreconcilable with many studies in literature that report specific – and even opposite – effects of cosolvents on protein-protein interactions [9], [18]–[23]. For instance, osmolytes such as glycerol and TMAO increase fibril formation of Aβ-peptide involved in Alzheimer's disease, but decrease aggregation of ataxin-3 involved in Machado-Joseph disease [18].…”

Section: Introductionmentioning

confidence: 99%

“…This dichotomy is, however, irreconcilable with many studies in literature that report specific – and even opposite – effects of cosolvents on protein-protein interactions [9], [18]–[23]. For instance, osmolytes such as glycerol and TMAO increase fibril formation of Aβ-peptide involved in Alzheimer's disease, but decrease aggregation of ataxin-3 involved in Machado-Joseph disease [18]. Another study reports that glycerol promotes the association of cytochrome c with cytochrome b5 but inhibits the association of cytochrome c and cytochrome c oxidase [19].…”

Section: Introductionmentioning

confidence: 99%

Quantifying the Molecular Origins of Opposite Solvent Effects on Protein-Protein Interactions

2013

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Although the nature of solvent-protein interactions is generally weak and non-specific, addition of cosolvents such as denaturants and osmolytes strengthens protein-protein interactions for some proteins, whereas it weakens protein-protein interactions for others. This is exemplified by the puzzling observation that addition of glycerol oppositely affects the association constants of two antibodies, D1.3 and D44.1, with lysozyme. To resolve this conundrum, we develop a methodology based on the thermodynamic principles of preferential interaction theory and the quantitative characterization of local protein solvation from molecular dynamics simulations. We find that changes of preferential solvent interactions at the protein-protein interface quantitatively account for the opposite effects of glycerol on the antibody-antigen association constants. Detailed characterization of local protein solvation in the free and associated protein states reveals how opposite solvent effects on protein-protein interactions depend on the extent of dewetting of the protein-protein contact region and on structural changes that alter cooperative solvent-protein interactions at the periphery of the protein-protein interface. These results demonstrate the direct relationship between macroscopic solvent effects on protein-protein interactions and atom-scale solvent-protein interactions, and establish a general methodology for predicting and understanding solvent effects on protein-protein interactions in diverse biological environments.

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Compacting Proteins: Pros and Cons of Osmolyte-Induced Folding

Cited by 13 publications

References 77 publications

Protein folding and stability in the presence of osmolytes

Protein folding and stability in the presence of osmolytes

Sucrose prevents protein fibrillation through compaction of the tertiary structure but hardly affects the secondary structure

Quantifying the Molecular Origins of Opposite Solvent Effects on Protein-Protein Interactions

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