Effect of site-specific amino acid D-isomerization on β-sheet transition and fibril formation profiles of Tau microtubule-binding repeat peptides.

Abstract d -amino acid-containing proteins have been found in several human tissues, and the spontaneous accumulation of d -amino acids in proteins is thought to be involved in age-dependent diseases including dementia. Tau, a microtubule-associated protein, is a major component of neurofibrillary tangles in Alzheimer's disease. Site-specific amino acid D-isomerization in Tau has been observed in the brains of patients with Alzheimer's disease. Here, we conducted amino acid D-isomerization at specific sites in microtubule-binding repeat peptides of Tau (Tau R2 and R3) and examined the effects on Tau structure and fibril formation. Our results demonstrate that amino acid D-isomerization in Tau R2 peptides decreased the rates of β-sheet transition and fibril formation compared with those of the wild-type peptide composed of all l -amino acids. In contrast, Tau R3 peptides that had undergone amino acid D-isomerization at either Asp314, Ser316, or Ser324 showed increased rates of β-sheet transition and fibril formation compared with those of the wild-type Tau R3 peptide. Highlights • Amino acid D-isomerization in Tau R2 and R3 controls β-sheet transition rate. • Fibril formation rate also depends on amino acid D-isomerization in Tau R2 and R3. • D-isomerization at Asp283 and/or Asp295 in Tau R2 reduces both these rates. • D-isomerization at Asp314, Ser316, or Ser324 in Tau R3 increases both these rates. • D-isomerization at Ser320 in Tau R3 reduces both these rates. [ABSTRACT FROM AUTHOR]