Structural changes in alpha-synuclein affect its chaperone-like activity in vitro.
Alpha-synuclein, a major constituent of Lewy bodies (LBs) in Parkinson's disease (PD), has been implicated to play a critical role in synaptic events, such as neuronal plasticity during development, learning, and degeneration under pathological conditions, although the physiological function of alpha-synuclein has not yet been established. We here present biochemical evidence that recombinant alpha-synuclein has a chaperone-like function against thermal and chemical stress in vitro. In our experiments, alpha-synuclein protected glutathione S-transferase (GST) and aldolase from heat-induced precipitation, and alpha-lactalbumin and bovine serum albumin from dithiothreitol (DTT)-induced precipitation like other molecular chaperones. Moreover, preheating of alpha-synuclein, which is believed to reorganize the molecular surface of alpha-synuclein, increased the chaperone-like activity. Interestingly, in organic solvents, which promotes the formation of secondary structure, alpha-synuclein aggregated more easily than in its native condition, which eventually might abrogate the chaperone-like function of the protein. In addition, alpha-synuclein was also rapidly and significantly precipitated by heat in the presence of Zn2+ in vitro, whereas it was not affected by the presence of Ca2+ or Mg2+. Circular dichroism spectra confirmed that alpha-synuclein underwent conformational change in the presence of Zn2+. Taken together, our data suggest that alpha-synuclein could act as a molecular chaperone, and that the conformational change of the alpha-synuclein could explain the aggregation kinetics of alpha-synuclein, which may be related to the abolishment of the chaperonic-like activity.
Kim
T D
TD
Department of Microbiology, Yonsei University College of Medicine, Seoul, Korea.
Paik
S R
SR
Yang
C H
CH
Kim
J
J
D000418:Albumins / Q000187:drug effects; D019281:Dimerization; D004229:Dithiothreitol / Q000494:pharmacology; D004798:Enzymes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000187:drug effects / Q000494:pharmacology*; D010300:Parkinson Disease / Q000209:etiology; D011489:Protein Denaturation / Q000187:drug effects; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000494:pharmacology; D013329:Structure-Activity Relationship; D051843:Synucleins; D013696:Temperature; D015032:Zinc / Q000494:pharmacology; D051844:alpha-Synuclein
D000418:Albumins; D004798:Enzymes; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D015032:Zinc; D004229:Dithiothreitol