Biological significance of isoaspartate and its repair system.
Isomerization of L-aspartate and deamidation of L-asparagine in proteins or peptides dominantly give rise to L-isoaspartate by a non-enzymatic reaction via succinimide as a intermediate under physiological conditions. Isoaspartates have been identified in a variety of cellular proteins in vivo as well as pathologically deposited proteins in neurodegenerative brain tissue. We described here that the formation of isoaspartate is enhanced in amyloid-beta (Abeta) peptides in Alzheimer's disease (AD). Specific antibodies recognizing isoaspartate of Abeta revealed that isomerized Abeta peptides were deposited in senile plaques as well as amyloid-bearing vessels. Moreover, it was revealed that Abeta peptides, isomerized at position 7 or 23, were differentially deposited in senile plaques and vascular amyloids in AD brains. In vitro experiments showed that the modification at position 23 greatly enhanced the aggregation of Abeta. Furthermore, systematic proline substitution analyses revealed that the beta-turn structure at positions 22 and 23 of Abeta42 plays a crucial role in the aggregation and neurotoxicity of Abeta peptides. It is suggested that spontaneous isomerization at position 23 induces the conformational change to form a beta-turn at position 23, which plays a pathogenic role in the deposition of Abeta peptides in sporadic AD. Protein L-isoaspartyl methyltransferase (PIMT) is a putative protein repair enzyme, which converts L-isoaspartyl residues in damaged proteins to normal L-aspartyl residues. PIMT-deficient mice manifested neurodegenerative changes concomitant with the accumulation of L-isoaspartate in the brain. We discuss here the pathological implications of the formation of isoaspartate in damaged proteins during neurodegeneration in model mice and AD.
Shimizu
Takahiko
T
Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Matsuoka
Yasuji
Y
Shirasawa
Takuji
T
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D006801:Humans; D026581:Isoaspartic Acid / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D058225:Plaque, Amyloid / Q000378:metabolism; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000172:deficiency / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D026581:Isoaspartic Acid; D011506:Proteins; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase