Limits...
Distinct stress conditions result in aggregation of proteins with similar properties.

Weids AJ, Ibstedt S, Tamás MJ, Grant CM - Sci Rep (2016)

Bottom Line: Protein aggregation is the abnormal association of proteins into larger aggregate structures which tend to be insoluble.This suggests that the proteins in aggregates are intrinsically aggregation-prone, rather than being proteins which are affected in a stress-specific manner.We suggest that similar mechanisms may apply in disease- and non-disease settings and that the factors and components that control protein aggregation may be evolutionary conserved.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.

ABSTRACT
Protein aggregation is the abnormal association of proteins into larger aggregate structures which tend to be insoluble. This occurs during normal physiological conditions and in response to age or stress-induced protein misfolding and denaturation. In this present study we have defined the range of proteins that aggregate in yeast cells during normal growth and after exposure to stress conditions including an oxidative stress (hydrogen peroxide), a heavy metal stress (arsenite) and an amino acid analogue (azetidine-2-carboxylic acid). Our data indicate that these three stress conditions, which work by distinct mechanisms, promote the aggregation of similar types of proteins probably by lowering the threshold of protein aggregation. The proteins that aggregate during physiological conditions and stress share several features; however, stress conditions shift the criteria for protein aggregation propensity. This suggests that the proteins in aggregates are intrinsically aggregation-prone, rather than being proteins which are affected in a stress-specific manner. We additionally identified significant overlaps between stress aggregating yeast proteins and proteins that aggregate during ageing in yeast and C. elegans. We suggest that similar mechanisms may apply in disease- and non-disease settings and that the factors and components that control protein aggregation may be evolutionary conserved.

No MeSH data available.


Related in: MedlinePlus

Properties of aggregation-prone proteins.(a) Abundance. The abundance of proteins (molecules/cell) in each set during non-stress conditions43 is plotted. (b) Expression levels. The codon adaptation index (CAI) is an indicator of gene expression level and the CAI for proteins in each set is plotted. (c) Protein size. The molecular weights (kDa) of proteins in each set is plotted. (d) Isoelectric point (pI). The pI values of the proteins in each set are shown. (e) Protein half-lives. The half-lives of proteins in each set under non-stress conditions25 is plotted. (f) Hydrophobicity. The GRAVY scores of the proteins in each set is plotted. Statistical analyses were performed as described in Methods, and *indicates a significant difference (p < 0.05) compared to the Unaggregated set.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834537&req=5

f3: Properties of aggregation-prone proteins.(a) Abundance. The abundance of proteins (molecules/cell) in each set during non-stress conditions43 is plotted. (b) Expression levels. The codon adaptation index (CAI) is an indicator of gene expression level and the CAI for proteins in each set is plotted. (c) Protein size. The molecular weights (kDa) of proteins in each set is plotted. (d) Isoelectric point (pI). The pI values of the proteins in each set are shown. (e) Protein half-lives. The half-lives of proteins in each set under non-stress conditions25 is plotted. (f) Hydrophobicity. The GRAVY scores of the proteins in each set is plotted. Statistical analyses were performed as described in Methods, and *indicates a significant difference (p < 0.05) compared to the Unaggregated set.

Mentions: Our previous observations suggested that arsenite stress lowers the overall threshold for protein aggregation15. To determine whether this is also true for other stresses that promote protein aggregation, we assessed a number of physicochemical properties of the proteins within our datasets. For comparison, a list of yeast proteins detectable by mass spectrometry in logarithmically growing cells was used to represent the properties of unaggregated proteins24. Aggregated proteins in the Unstressed-set are more abundant (i.e. present in more molecules/cell), more highly expressed (indicated by a high codon adaptation index (CAI)), smaller in size (i.e. lower molecular weight (MW)), and have a higher isoelectric point (pI) than proteins in the Unaggregated set (Fig. 3a–d). Similar to the Unstressed-set, highly expressed and abundant proteins are significantly enriched in the aggregate fractions following all three stress conditions (Fig. 3a,b). However, the proteins which aggregate under stress conditions have considerably lower abundance and expression levels compared with the Unstressed-set (Fig. 3a,b). Proteins that aggregate following the three stress conditions also have a lower pI than the proteins in the Unstressed set; their pIs are similar to the Unaggregated-set (H2O2-set and As-set) or lower (Common-set and AZC-set) (Fig. 3d). Stress-specific differences are also found when the sizes of the aggregated proteins are compared (Fig. 3c). Whilst the proteins in the Unstressed-set are generally smaller in size than the unaggregated set, proteins which aggregate in the Common-set, H2O2-set and AZC-set are significantly larger than those in the Unstressed-set. Thus, the proteins that aggregate following stress conditions have lower expression levels, are less abundant, are more acidic and are larger than the proteins which aggregate during physiological non-stress conditions.


Distinct stress conditions result in aggregation of proteins with similar properties.

Weids AJ, Ibstedt S, Tamás MJ, Grant CM - Sci Rep (2016)

Properties of aggregation-prone proteins.(a) Abundance. The abundance of proteins (molecules/cell) in each set during non-stress conditions43 is plotted. (b) Expression levels. The codon adaptation index (CAI) is an indicator of gene expression level and the CAI for proteins in each set is plotted. (c) Protein size. The molecular weights (kDa) of proteins in each set is plotted. (d) Isoelectric point (pI). The pI values of the proteins in each set are shown. (e) Protein half-lives. The half-lives of proteins in each set under non-stress conditions25 is plotted. (f) Hydrophobicity. The GRAVY scores of the proteins in each set is plotted. Statistical analyses were performed as described in Methods, and *indicates a significant difference (p < 0.05) compared to the Unaggregated set.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834537&req=5

f3: Properties of aggregation-prone proteins.(a) Abundance. The abundance of proteins (molecules/cell) in each set during non-stress conditions43 is plotted. (b) Expression levels. The codon adaptation index (CAI) is an indicator of gene expression level and the CAI for proteins in each set is plotted. (c) Protein size. The molecular weights (kDa) of proteins in each set is plotted. (d) Isoelectric point (pI). The pI values of the proteins in each set are shown. (e) Protein half-lives. The half-lives of proteins in each set under non-stress conditions25 is plotted. (f) Hydrophobicity. The GRAVY scores of the proteins in each set is plotted. Statistical analyses were performed as described in Methods, and *indicates a significant difference (p < 0.05) compared to the Unaggregated set.
Mentions: Our previous observations suggested that arsenite stress lowers the overall threshold for protein aggregation15. To determine whether this is also true for other stresses that promote protein aggregation, we assessed a number of physicochemical properties of the proteins within our datasets. For comparison, a list of yeast proteins detectable by mass spectrometry in logarithmically growing cells was used to represent the properties of unaggregated proteins24. Aggregated proteins in the Unstressed-set are more abundant (i.e. present in more molecules/cell), more highly expressed (indicated by a high codon adaptation index (CAI)), smaller in size (i.e. lower molecular weight (MW)), and have a higher isoelectric point (pI) than proteins in the Unaggregated set (Fig. 3a–d). Similar to the Unstressed-set, highly expressed and abundant proteins are significantly enriched in the aggregate fractions following all three stress conditions (Fig. 3a,b). However, the proteins which aggregate under stress conditions have considerably lower abundance and expression levels compared with the Unstressed-set (Fig. 3a,b). Proteins that aggregate following the three stress conditions also have a lower pI than the proteins in the Unstressed set; their pIs are similar to the Unaggregated-set (H2O2-set and As-set) or lower (Common-set and AZC-set) (Fig. 3d). Stress-specific differences are also found when the sizes of the aggregated proteins are compared (Fig. 3c). Whilst the proteins in the Unstressed-set are generally smaller in size than the unaggregated set, proteins which aggregate in the Common-set, H2O2-set and AZC-set are significantly larger than those in the Unstressed-set. Thus, the proteins that aggregate following stress conditions have lower expression levels, are less abundant, are more acidic and are larger than the proteins which aggregate during physiological non-stress conditions.

Bottom Line: Protein aggregation is the abnormal association of proteins into larger aggregate structures which tend to be insoluble.This suggests that the proteins in aggregates are intrinsically aggregation-prone, rather than being proteins which are affected in a stress-specific manner.We suggest that similar mechanisms may apply in disease- and non-disease settings and that the factors and components that control protein aggregation may be evolutionary conserved.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.

ABSTRACT
Protein aggregation is the abnormal association of proteins into larger aggregate structures which tend to be insoluble. This occurs during normal physiological conditions and in response to age or stress-induced protein misfolding and denaturation. In this present study we have defined the range of proteins that aggregate in yeast cells during normal growth and after exposure to stress conditions including an oxidative stress (hydrogen peroxide), a heavy metal stress (arsenite) and an amino acid analogue (azetidine-2-carboxylic acid). Our data indicate that these three stress conditions, which work by distinct mechanisms, promote the aggregation of similar types of proteins probably by lowering the threshold of protein aggregation. The proteins that aggregate during physiological conditions and stress share several features; however, stress conditions shift the criteria for protein aggregation propensity. This suggests that the proteins in aggregates are intrinsically aggregation-prone, rather than being proteins which are affected in a stress-specific manner. We additionally identified significant overlaps between stress aggregating yeast proteins and proteins that aggregate during ageing in yeast and C. elegans. We suggest that similar mechanisms may apply in disease- and non-disease settings and that the factors and components that control protein aggregation may be evolutionary conserved.

No MeSH data available.


Related in: MedlinePlus