Copper(II)-induced self-oligomerization of alpha-synuclein.
alpha-Synuclein is a component of the abnormal protein depositions in senile plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease respectively. The protein was suggested to provide a possible nucleation centre for plaque formation in AD via selective interaction with amyloid beta/A4 protein (Abeta). We have shown previously that alpha-synuclein has experienced self-oligomerization when Abeta25-35 was present in an orientation-specific manner in the sequence. Here we examine this biochemically specific self-oligomerization with the use of various metals. Strikingly, copper(II) was the most effective metal ion affecting alpha-synuclein to form self-oligomers in the presence of coupling reagents such as dicyclohexylcarbodi-imide or N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The size distribution of the oligomers indicated that monomeric alpha-synuclein was oligomerized sequentially. The copper-induced oligomerization was shown to be suppressed as the acidic C-terminus of alpha-synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the Abeta25-35-induced oligomerizations of the intact and truncated forms of alpha-synuclein were not affected. This clearly indicated that the copper-induced oligomerization was dependent on the acidic C-terminal region and that its underlying biochemical mechanism was distinct from that of the Abeta25-35-induced oligomerization. Although the physiological or pathological relevance of the oligomerization remains currently elusive, the common outcome of alpha-synuclein on treatment with copper or Abeta25-35 might be useful in understanding neurodegenerative disorders in molecular terms. In addition, abnormal copper homoeostasis could be considered as one of the risk factors for the development of disorders such as AD or Parkinson's disease.
Paik
S R
SR
Department of Biochemistry, College of Medicine, Inha University, 253 Yonghyun-Dong, Nam-Ku, Inchon 402-751, Korea. srpaik@dragon.inha.ac.kr
Shin
H J
HJ
Lee
J H
JH
Chang
C S
CS
Kim
J
J
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D001665:Binding Sites; D002412:Cations / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000494:pharmacology*; D004024:Dicyclohexylcarbodiimide / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D013058:Mass Spectrometry; D008666:Metalloendopeptidases; D008670:Metals / Q000494:pharmacology; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D016229:Amyloid beta-Peptides; D002412:Cations; D008670:Metals; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011804:Quinolines; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C074636:amyloid beta-protein (25-35); D004024:Dicyclohexylcarbodiimide; C000470:EEDQ; D003300:Copper; D010450:Endopeptidases; D008666:Metalloendopeptidases; C058921:endoproteinase Asp-N