Characterisation of amyloid fibril formation by small heat-shock chaperone proteins human alphaA-, alphaB- and R120G alphaB-crystallins.
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.
Department of Chemistry, University of Cambridge, Cambridge, UK.
Sarah
S
Meehan
Tuomas P J
TP
Knowles
Andrew J
AJ
Baldwin
Jeffrey F
JF
Smith
Adam M
AM
Squires
Phillip
P
Clements
Teresa M
TM
Treweek
Heath
H
Ecroyd
Gian Gaetano
GG
Tartaglia
Michele
M
Vendruscolo
Cait E
CE
Macphee
Christopher M
CM
Dobson
John A
JA
Carver
D000682:Amyloid / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D018625:Microscopy, Atomic Force; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D038202:alpha-Crystallin A Chain / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D038203:alpha-Crystallin B Chain / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D000682:Amyloid; D038202:alpha-Crystallin A Chain; D038203:alpha-Crystallin B Chain