The effect of small molecules in modulating the chaperone activity of alphaB-crystallin against ordered and disordered protein aggregation.
Protein aggregation can proceed via disordered or ordered mechanisms, with the latter being associated with amyloid fibril formation, which has been linked to a number of debilitating conditions including Alzheimer's, Parkinson's and Creutzfeldt-Jakob diseases. Small heat-shock proteins (sHsps), such as alphaB-crystallin, act as chaperones to prevent protein aggregation and are thought to play a key role in the prevention of protein-misfolding diseases. In this study, we have explored the potential for small molecules such as arginine and guanidine to affect the chaperone activity of alphaB-crystallin against disordered (amorphous) and ordered (amyloid fibril) forms of protein aggregation. The effect of these additives is highly dependent upon the target protein undergoing aggregation. Importantly, our results show that the chaperone action of alphaB-crystallin against aggregation of the disease-related amyloid fibril forming protein alpha-synucleinA53T is enhanced in the presence of arginine and similar positively charged compounds (such as lysine and guanidine). Thus, our results suggest that target protein identity plays a critical role in governing the effect of small molecules on the chaperone action of sHsps. Significantly, small molecules that regulate the activity of sHsps may provide a mechanism to protect cells from the toxic protein aggregation that is associated with some protein-misfolding diseases.
Ecroyd
Heath
H
School of Chemistry and Physics, The University of Adelaide, Australia. heath.ecroyd@adelaide.edu.au
Carver
John A
JA
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D002364:Caseins / Q000737:chemistry; D002417:Cattle; D019610:Cytoprotection; D019791:Guanidine / Q000494:pharmacology*; D006358:Hot Temperature; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D007768:Lactalbumin / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D038203:alpha-Crystallin B Chain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D002364:Caseins; D007328:Insulin; D038203:alpha-Crystallin B Chain; D051844:alpha-Synuclein; D007768:Lactalbumin; D001120:Arginine; D019791:Guanidine