αB‐crystallin competes with Alzheimer's disease β‐amyloid peptide for peptide–peptide interactions and induces oxidation of Abeta‐Met35

Abstract

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 b-amyloid (Ab). Except for Ab, plaques contain several other components which co-precipitate together with Ab. One such component is the small heat shock protein (sHSP) aB-crystallin. Instead of preventing the cell from the neurotoxicity of Ab, aB-crystallin induces an increased neurotoxicity.We find -using solution state NMR spectroscopy -that aBcrystallin competes efficiently for Ab monomer-monomer interactions. Interactions between Ab and aB-crystallin involve the hydrophobic core residues 17-21 as well as residues 31-32 of Ab, and thus the same chemical groups which are important for Ab aggregation. In the presence of aB-crystallin, Met35 in Ab becomes efficiently oxidized. In order to quantify the redox properties of the different complexes consisting of Ab/aB-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 Ab might account for the increased neurotoxicity and the inability of Ab to form fibrillar structures, which has been observed previously in the presence of aB-crystallin [Stege, G.J. et al. (1999) The molecular chaperone aB-crystallin enhances amyloid-beta neurotoxicity. Biochem. Biophys. Res. Commun. 262,[152][153][154][155][156].

Crystallin proteins and amyloid fibrils

“…KFVIF; the corresponding peptide region in αB-crystallin is RFSVN) has strong sequence similarity to a region of the fibril-forming core domain of Aβ(1-40), KLVFF [102,141]. This region in Aβ(1-40) has recently been shown by NMR spectroscopy to be primarily involved in the interaction between Aβ(1-40) and αB-crystallin [142]. Moreover, KLVFF of Aβ(1-40) facilitates the elongation of fibrils formed from Aβ.…”

Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists

“…Investigation of the dynamics of the C-terminus of αB-crystallin showed the importance of this region for the solubility of αB-crystallin complexes [300]. Saturation transfer difference (STD) experiments showed that αB-crystallin interacts with the hydrophobic core of A [301]. Furthermore, the ability of αB-crystallin to prevent oligomerization and the oxidation of Met35 was established, whereas the oxidation of Met35 in A induces an increased neurotoxicity, since the oxidized form facilitates the propagation of free radicals among adjacent residues [301][302][303].…”

“…Saturation transfer difference (STD) experiments showed that αB-crystallin interacts with the hydrophobic core of A [301]. Furthermore, the ability of αB-crystallin to prevent oligomerization and the oxidation of Met35 was established, whereas the oxidation of Met35 in A induces an increased neurotoxicity, since the oxidized form facilitates the propagation of free radicals among adjacent residues [301][302][303]. Based on combined NMR, PRE and relaxation experiments, as well as mass spectroscopy, a comprehensive picture of αB-crystallin emerges in which quaternary dynamics and oligomeric distribution due to monomer exchange on a timescale of minutes are connected to structural fluctuations in the C-terminus on the millisecond timescale [304,305].…”

Small Amphipathic Molecules Modulate Secondary Structure and Amyloid Fibril-forming Kinetics of Alzheimer Disease Peptide Aβ1–42

“…On the basis of previous work on various other small molecule modulators of A␤ aggregation, such as 8-hydroxyquinolines (42), oleuropein (43,44), ␣-helix stabilizers (45), various chaperones (46,47), anesthetics (48,49), and gangliosides (50), two potential binding sites can be suggested. From these previous studies it is clear that A␤ contains a small molecule binding site near residues 10 -20 and a second binding site in the C-terminal glycine zipper motif.…”