Despite the regulatory role of Tau protein in the stabilization and assembly of microtubules, this protein has an important function in the protection and stabilizing of DNA molecules in the cell nucleus. In the present study, it has been indicated that glycation of lysine residues (Lys-267, Lys-274, and Lys-280) in the microtubule-binding domain (MBD) can considerably decrease its binding affinity to DNA molecules. The structural analysis also confirmed that the decreased glycated tau-DNA complex's stability was due to structural modification of this protein after the glycation process. The study of hippocampal cells under hyperglycemic conditions showed that near to 70% of Tau proteins glycated in these cells, although the expression of Tau remained unaffected. The assessment of H3K9me2, as a marker for binding of Tau to pericentromeric heterochromatin (PCH), indicated that localization of Tau protein on PCH was remarkably decreased at high glucose conditions relative to the controls. It is suggested that increasing the structural stability of Tau protein limits the ability of this protein for DNA binding, while the molecular and physical barrier of glycated Lys residues should not be neglected.
Keywords: Binding affinity; DNA binding; H3K9me2; Non-enzymatic glycation; PCH; Tau protein.
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