alphaB-crystallin competes with Alzheimer's disease beta-amyloid peptide for peptide-peptide interactions and induces oxidation of Abeta-Met35.
Alzheimer's disease (AD) is associated with plaque deposition in the brain of AD patients. The major component of the aggregate is a 39-42 long peptide termed beta-amyloid (Abeta). Except for Abeta, plaques contain several other components which co-precipitate together with Abeta. One such component is the small heat shock protein (sHSP) alphaB-crystallin. Instead of preventing the cell from the neurotoxicity of Abeta, alphaB-crystallin induces an increased neurotoxicity. We find - using solution state NMR spectroscopy - that alphaB-crystallin competes efficiently for Abeta monomer-monomer interactions. Interactions between Abeta and alphaB-crystallin involve the hydrophobic core residues 17-21 as well as residues 31-32 of Abeta, and thus the same chemical groups which are important for Abeta aggregation. In the presence of alphaB-crystallin, Met35 in Abeta becomes efficiently oxidized. In order to quantify the redox properties of the different complexes consisting of Abeta/alphaB-crystallin/copper, we suggest an NMR assay which allows to estimate the electrochemical properties indirectly by monitoring the rate of glutathion (GSH) auto-oxidation. The oxidation of the side chain Met35 in Abeta might account for the increased neurotoxicity and the inability of Abeta to form fibrillar structures, which has been observed previously in the presence of alphaB-crystallin [Stege, G.J. et al. (1999) The molecular chaperone alphaB-crystallin enhances amyloid-beta neurotoxicity. Biochem. Biophys. Res. Commun. 262, 152-156.].
Narayanan
Saravanakumar
S
Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse, 10, 13125 Berlin, Germany.
Kamps
Bram
B
Boelens
Wilbert C
WC
Reif
Bernd
B
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001667:Binding, Competitive; D002942:Circular Dichroism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008715:Methionine / Q000737:chemistry; D046912:Multiprotein Complexes; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000737:chemistry* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D038203:alpha-Crystallin B Chain; D008715:Methionine