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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

Molecular chaperones present in the aggregates.Molecular chaperones were identified within the datasets and the overlap between the datasets is presented. The chaperone types are indicated by colour of the text.
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f6: Molecular chaperones present in the aggregates.Molecular chaperones were identified within the datasets and the overlap between the datasets is presented. The chaperone types are indicated by colour of the text.

Mentions: Given that proteins with multiple chaperone interactions are enriched within stress-aggregated sets, we examined whether chaperones were isolated in our aggregate fractions. It should be emphasised that our analysis does not allow us to differentiate between chaperones which are functional components of the aggregates, versus chaperones which are themselves aggregation-prone. Of the 63 known chaperones in S. cerevisiae29, we identified 30 chaperones distributed between all the datasets: 11 Hsp70 s, five Hsp40 s, seven chaperonin subunits, three AAA+ family members, two Hsp90 s, one Hsp60 and one small Hsp chaperone (Fig. 6). A total of seven chaperones are present in the Unstressed-set: Ssb1, Ssa1, Ssa4, Ssc1, Hsp82, Hsc82 and Sec63. We also identified chaperones within the non-overlapping stress sets. The Common-set included 19 chaperones spanning all six chaperone classes (Fig. 6). All of these chaperones except Ssc1, Hsp78, Hsp60 and Sec63, are present in the cytoplasm. Their inclusion within the Common-set may indicate that these chaperones are part of a general cytoplasmic response to stress and that they are associated with their client proteins. Seven chaperones were identified within the AZC-specific set; four of these (Ssa2, Ssa3, Sse2, Kar2) belong to the Hsp70 family, whilst one (Mdj1) is a known co-factor of proteins of the Hsp70 family (Fig. 6). This may be indicative of the mechanism of action of AZC, as Hsp70 family proteins are important for co-translational folding. Two chaperones were present in the As-specific set (Zuo1 and Ssb2), and both are ribosome-associated chaperones (Fig. 6). This is in agreement with the notion that arsenite primarily targets nascent proteins for aggregation. The H2O2-specific set contained two chaperones (Cct6 and Mcx1) but it is currently unclear how these chaperones relate to H2O2’s mode of action. The H2O2-set was enriched for proteins that interact with Ssz1 – however, this chaperone is absent from the aggregates themselves. This may suggest that H2O2 might inhibit Ssz1 function.


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

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

Molecular chaperones present in the aggregates.Molecular chaperones were identified within the datasets and the overlap between the datasets is presented. The chaperone types are indicated by colour of the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Molecular chaperones present in the aggregates.Molecular chaperones were identified within the datasets and the overlap between the datasets is presented. The chaperone types are indicated by colour of the text.
Mentions: Given that proteins with multiple chaperone interactions are enriched within stress-aggregated sets, we examined whether chaperones were isolated in our aggregate fractions. It should be emphasised that our analysis does not allow us to differentiate between chaperones which are functional components of the aggregates, versus chaperones which are themselves aggregation-prone. Of the 63 known chaperones in S. cerevisiae29, we identified 30 chaperones distributed between all the datasets: 11 Hsp70 s, five Hsp40 s, seven chaperonin subunits, three AAA+ family members, two Hsp90 s, one Hsp60 and one small Hsp chaperone (Fig. 6). A total of seven chaperones are present in the Unstressed-set: Ssb1, Ssa1, Ssa4, Ssc1, Hsp82, Hsc82 and Sec63. We also identified chaperones within the non-overlapping stress sets. The Common-set included 19 chaperones spanning all six chaperone classes (Fig. 6). All of these chaperones except Ssc1, Hsp78, Hsp60 and Sec63, are present in the cytoplasm. Their inclusion within the Common-set may indicate that these chaperones are part of a general cytoplasmic response to stress and that they are associated with their client proteins. Seven chaperones were identified within the AZC-specific set; four of these (Ssa2, Ssa3, Sse2, Kar2) belong to the Hsp70 family, whilst one (Mdj1) is a known co-factor of proteins of the Hsp70 family (Fig. 6). This may be indicative of the mechanism of action of AZC, as Hsp70 family proteins are important for co-translational folding. Two chaperones were present in the As-specific set (Zuo1 and Ssb2), and both are ribosome-associated chaperones (Fig. 6). This is in agreement with the notion that arsenite primarily targets nascent proteins for aggregation. The H2O2-specific set contained two chaperones (Cct6 and Mcx1) but it is currently unclear how these chaperones relate to H2O2’s mode of action. The H2O2-set was enriched for proteins that interact with Ssz1 – however, this chaperone is absent from the aggregates themselves. This may suggest that H2O2 might inhibit Ssz1 function.

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