Characterisation of amyloid fibril formation by small heat-shock proteins, human alphaA-, alphaB- and R120G alphaB-crystallins

Sarah Meehan
Tuomas P. Knowles, University of Cambridge
Andrew J. Baldwin, University of Cambridge
Jeffrey F. Smith, University of Cambridge
Adam M. Squires, University of Reading
Phillip Clements, University of Adelaide
Teresa M. Treweek, University of Wollongong
Heath W. Ecroyd, University of Wollongong
Gian Tartaglia, University of Cambridge
Michele Vendruscolo, University of Cambridge
Cait MacPhee
Christopher Dobson
John Carver

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Meehan, S., Knowles, T. P., Baldwin, A. J., Smith, J. F., Squires, A. M., Clements, P., Treweek, T. M., Ecroyd, H. W., Tartaglia, G., Vendruscolo, M., MacPhee, C., Dobson, C. & Carver, J. (2007). Characterisation of amyloid fibril formation by small heat-shock proteins, human alphaA-, alphaB- and R120G alphaB-crystallins. Journal of Molecular Biology, 372 (2), 470-484.

Abstract

AlphaB-Crystallin is a ubiquitous small heat-shock protein (sHsp) renowned for its chaperone ability to prevent target protein aggregation. It is stress-inducible and its up-regulation is associated with a number of disorders, including those linked to the deposition of misfolded proteins, such as Alzheimer's and Parkinson's diseases. We have characterised the formation of amyloid fibrils by human alphaB-crystallin in detail, and also that of alphaA-crystallin and the disease-related mutant R120G alphaB-crystallin. We find that the last 12 amino acid residues of the C-terminal region of alphaB-crystallin are predicted from their physico-chemical properties to have a very low propensity to aggregate. (1)H NMR spectroscopy reveals that this hydrophilic C-terminal region is flexible both in its solution state and in amyloid fibrils, where it protrudes from the fibrillar core. We demonstrate, in addition, that the equilibrium between different protofilament assemblies can be manipulated and controlled in vitro to select for particular alphaB-crystallin amyloid morphologies. Overall, this study suggests that there could be a fine balance in vivo between the native functional sHsp state and the formation of amyloid fibrils.