C-terminal truncation modulates both nucleation and extension phases of tau fibrillization |
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Authors: | Yin Haishan Kuret Jeff |
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Institution: | a Ohio State Biochemistry Program, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA b Center for Molecular Neurobiology, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA |
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Abstract: | Proteolytic post-translational modification has been proposed as an early stage event in the aggregation of τ protein and formation of neurofibrillary lesions in Alzheimer’s disease. Caspases and other proteases cleave τ in vivo at discrete locations including Asp421 and Glu391. Both cleavage products are prone to aggregation relative to wild-type, full-length τ protein. To determine the mechanism underlying this effect, the fibrillization of τ truncated after Asp421 and Glu391 residues was characterized in a full-length four-repeat τ background using quantitative electron microscopy methods under homogeneous nucleation conditions. Both C-terminal truncations decreased critical concentration relative to full-length τ, resulting in more filament mass at reaction plateau. Moreover, truncation directly augmented the efficiency of the nucleation reaction. The results suggest the mechanism through which C-terminal proteolysis can modulate τ filament accumulation depending on whether it precedes or follows nucleation. |
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Keywords: | Amyloid τ Fibrillization Kinetics Proteolysis Alzheimer&rsquo s disease |
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