Abstract
Small heat-shock proteins (sHsps), such as αB-crystallin, are one of the major classes of molecular chaperone proteins. In vivo, under conditions of cellular stress, sHsps are the principal defence proteins that prevent large-scale protein aggregation. Progress in determining the structure of sHsps has been significant recently, particularly in relation to the conserved, central and β-sheet structured α-crystallin domain (ACD). However, an understanding of the structure and functional roles of the N- and C-terminal flanking regions has proved elusive mainly because of their unstructured and dynamic nature. In this paper, we propose functional roles for both flanking regions, based around three properties: (i) they act in a localised crowding manner to regulate interactions with target proteins during chaperone action, (ii) they protect the ACD from deleterious amyloid fibril formation and (iii) the flexibility of these regions, particularly at the extreme C-terminus in mammalian sHsps, provides solubility for sHsps under chaperone and non-chaperone conditions. In the eye lens, these properties are highly relevant as the crystallin proteins, in particular the two sHsps αA- and αB-crystallin, are present at very high concentrations.
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Abbreviations
- ACD:
-
α-Crystallin domain
- αAc:
-
αA-Crystallin
- αBc:
-
αB-Crystallin
- IF:
-
Intermediate filament
- NAC:
-
Non-amyloid-β component
- sHsps:
-
Small heat-shock proteins
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Acknowledgements
The Australian National Health and Medical Research Council is thanked for financial support via a project grant to JAC. ABG acknowledges the financial support of an Australian Postgraduate Award. We thank Prof. Yuji Goto, Osaka University, Prof. Roger Truscott, University of Wollongong and Dr. Nicholas Ray and Dr. David Thorn, Australian National University, for the helpful discussions relating to crystallin protein interactions in the eye lens. JAC is indebted to Simon Tognetti whose creative drawings and pottery inspired some of the ideas presented herein.
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Figure S1
ZipperDB analysis (Goldschmidt et al. 2010) of the amino acid sequences of the ten human sHsps. The N-terminal, ACD, and C-terminal regions are segmented by the black vertical dashed lines in that sequential order. The blue, green, yellow and orange lines are hexapeptide residues that are of increasing Rosetta energy, whilst the red lines that cross the threshold of −23 kcal/mol (black horizontal line) are those residues associated with a hexapeptide that has a high propensity of forming amyloid fibrils. (DOCX 88 kb)
Supplementary Table 1
Comparison of the predicted fibril-forming or β-aggregation propensity of all ten human sHsps and two E. coli sHsps using three different prediction algorithms, i.e. ZipperDB (Goldschmidt et al. 2010), TANGO (Fernandez-Escamilla et al. 2004) and Zyggregator (Tartaglia et al. 2008). Percentages are given as the number of residues classified as having a ‘high propensity’ to form fibrils within a specific region over all the residues within that specific region of the protein, e.g. the N-terminal, ACD or C-terminal regions. (DOCX 38.5 kb)
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Carver, J.A., Grosas, A.B., Ecroyd, H. et al. The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins. Cell Stress and Chaperones 22, 627–638 (2017). https://doi.org/10.1007/s12192-017-0789-6
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DOI: https://doi.org/10.1007/s12192-017-0789-6