Characterisation of amyloid fibril formation by small heat-shock chaperone proteins human αA-, αB and R120G αB-crystallins
Date
2007
Authors
Meehan, S.
Knowles, T.
Baldwin, A.
Smith, J.
Squires, A.
Clements, P.
Treweek, T.
Ecroyd, H.
Tartaglia, G.
Vendruscolo, M.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Molecular Biology, 2007; 372(2):470-484
Statement of Responsibility
Sarah Meehan, Tuomas P.J. Knowles, Andrew J. Baldwin, Jeffrey F. Smith, Adam M. Squires, Phillip Clements, Teresa M. Treweek, Heath Ecroyd, Gian Gaetano Tartaglia, Michele Vendruscolo, Cait E. MacPhee, Christopher M. Dobson and John A. Carver
Conference Name
Abstract
αB-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 aB-crystallin in detail, and also that of aA-crystallin and the disease-related mutant R120G aB-crystallin. We find that the last 12 amino acid residues of the C-terminal region of aB-crystallin are predicted from their physico-chemical properties to have a very low propensity to aggregate. 1H 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 aB-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.