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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

Functional analysis of aggregation-prone proteins.Significantly enriched functional categories within the data-sets were determined using FunCat (FDR < 5%). Results are ordered on MIPS category classification numbers and overarching categories are in capitals.
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f2: Functional analysis of aggregation-prone proteins.Significantly enriched functional categories within the data-sets were determined using FunCat (FDR < 5%). Results are ordered on MIPS category classification numbers and overarching categories are in capitals.

Mentions: We first performed gene ontology analysis to examine what functional categories of proteins are enriched in the aggregate fractions following the three distinct stress conditions. For this and all subsequent analyses, our stress datasets were compared with an unstressed dataset, which is comprised of proteins that aggregate only under normal physiological conditions (Unstressed-set). Significantly enriched (5% FDR) functional categories were determined within the datasets using the MIPS Functional Catalogue23. As we previously described15, factors involved in protein synthesis including ribosomal and translation related proteins are strongly enriched within proteins that aggregate in the absence of stress (Fig. 2; Unstressed dataset). Additionally, proteins involved in energy and transport functions are enriched within these aggregates. More functional categories were enriched in the Common-set compared with the Unstressed-set; these include many protein synthesis related functions, as well as proteins involved in metabolism and energy related processes. There was also enrichment for proteins involved in protein folding, stabilisation and processing, as well as components of the unfolded protein response. These latter classes of proteins would be expected to constitute part of the cellular response to protein misfolding and aggregation. Stress-specific differences were found in the functional classes that are enriched under different stress conditions. The As-specific set was significantly enriched for proteins related to protein synthesis and translation (Fig. 2), in line with the notion that arsenite interferes with folding of nascent polypeptides1516. The AZC-specific set was enriched in a large number of categories, including metabolism, energy and protein synthesis-related functions, as well as cell rescue and defence proteins including a number of chaperones (Fig. 2). The large number of functional groups enriched in the AZC-specific data-set may be a reflection of its mode of action, as AZC will affect all proline-containing proteins. In contrast to the other sets, no functional groups were significantly enriched within the H2O2-specific set. Taken together, these data indicate that protein aggregates isolated from different conditions show enrichment for a number of similar functional categories.


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

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

Functional analysis of aggregation-prone proteins.Significantly enriched functional categories within the data-sets were determined using FunCat (FDR < 5%). Results are ordered on MIPS category classification numbers and overarching categories are in capitals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Functional analysis of aggregation-prone proteins.Significantly enriched functional categories within the data-sets were determined using FunCat (FDR < 5%). Results are ordered on MIPS category classification numbers and overarching categories are in capitals.
Mentions: We first performed gene ontology analysis to examine what functional categories of proteins are enriched in the aggregate fractions following the three distinct stress conditions. For this and all subsequent analyses, our stress datasets were compared with an unstressed dataset, which is comprised of proteins that aggregate only under normal physiological conditions (Unstressed-set). Significantly enriched (5% FDR) functional categories were determined within the datasets using the MIPS Functional Catalogue23. As we previously described15, factors involved in protein synthesis including ribosomal and translation related proteins are strongly enriched within proteins that aggregate in the absence of stress (Fig. 2; Unstressed dataset). Additionally, proteins involved in energy and transport functions are enriched within these aggregates. More functional categories were enriched in the Common-set compared with the Unstressed-set; these include many protein synthesis related functions, as well as proteins involved in metabolism and energy related processes. There was also enrichment for proteins involved in protein folding, stabilisation and processing, as well as components of the unfolded protein response. These latter classes of proteins would be expected to constitute part of the cellular response to protein misfolding and aggregation. Stress-specific differences were found in the functional classes that are enriched under different stress conditions. The As-specific set was significantly enriched for proteins related to protein synthesis and translation (Fig. 2), in line with the notion that arsenite interferes with folding of nascent polypeptides1516. The AZC-specific set was enriched in a large number of categories, including metabolism, energy and protein synthesis-related functions, as well as cell rescue and defence proteins including a number of chaperones (Fig. 2). The large number of functional groups enriched in the AZC-specific data-set may be a reflection of its mode of action, as AZC will affect all proline-containing proteins. In contrast to the other sets, no functional groups were significantly enriched within the H2O2-specific set. Taken together, these data indicate that protein aggregates isolated from different conditions show enrichment for a number of similar functional categories.

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