Racemization of the amyloidal beta Asp1 residue blocks the acceleration of fibril formation caused by racemization of the Asp23 residue.
Amyloid beta proteins extracted from the amyloid cores of neuritic plaques are considerably racemized at their Asp residues. To assess the impact of D-Asp on amyloid beta(1-42) conformation and on initiation of amyloid fibril formation, we used wild-type amyloid beta(1-42) and analogs in which D-Asp was substituted for L-Asp at residues 1, 7, 23, and all combinations of these residues. Amyloid fibril formation was enhanced by D-Asp23; modulation of Asp chirality at N-terminal position 1 blocked this enhancement and modulation at position 7 augmented it. Knowledge of such chirality modifications may help to develop potent inhibitors of amyloid fibril formation.
Sakai-Kato
Kumiko
K
Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. kumikato@musashino-u.ac.jp
Naito
Megumi
M
Utsunomiya-Tate
Naoko
N
D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure*; D001224:Aspartic Acid / Q000737:chemistry*; D019281:Dimerization; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D001224:Aspartic Acid