Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues - PubMed (original) (raw)
. 1994 Apr 8;269(14):10205-8.
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- PMID: 8144598
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Racemization of Asp23 residue affects the aggregation properties of Alzheimer amyloid beta protein analogues
T Tomiyama et al. J Biol Chem. 1994.
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Abstract
The beta proteins in amyloid deposits of Alzheimer's disease have been found to be racemized and/or isomerized at their Asp residues (Roher, A. E., Lowenson, J. D., Clarke, S., Wolkow, C., Wang, R., Cotter, R. J., Reardon, I. M., Zurcher-Neely, H. A., Heinrikson, R. L., Ball, M. J., and Greenberg, B. D. (1993) J. Biol. Chem. 268, 3072-3083). To elucidate the effect of racemization on the aggregation properties of beta proteins, we synthesized four beta protein analogues in which D-Asp was substituted for L-Asp residues, i.e. normal beta 1-35, [D-Asp7]beta 1-35, [D-Asp23]beta 1-35, and [D-Asp7,D-Asp23]beta 1-35. The aggregation and fibril formation of the peptides were examined by means of spectrophotometry, sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE), and electron microscopy. Of the four peptides, [D-Asp23]beta 1-35 showed the earliest increase in turbidity and appearance of a smear in SDS-PAGE. This was followed by [D-Asp7,D-Asp23]beta 1-35 and normal beta 1-35. [D-Asp7]beta 1-35 was considerably delayed in showing these signs of aggregation. Corresponding with the increase in turbidity and the appearance of a smear in SDS-PAGE, fibril formation was observed in electron microscopy. These results reveal that the aggregation properties of beta 1-35 peptides are affected by racemization of their Asp residues depending on their position. Racemization at amino acid position 23 accelerated the peptide aggregation and fibril formation, while that at position 7 slowed down this reaction. This suggests that the site-specific racemization of beta protein may be involved in the amyloid fibril formation in Alzheimer's disease.
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