title: C-terminal truncation modulates both nucleation and extension phases of tau fibrillization.
abstract: Proteolytic post-translational modification has been proposed as an early stage event in the aggregation of tau protein and formation of neurofibrillary lesions in Alzheimer's disease. Caspases and other proteases cleave tau in vivo at discrete locations including Asp421 and Glu391. Both cleavage products are prone to aggregation relative to wild-type, full-length tau protein. To determine the mechanism underlying this effect, the fibrillization of tau truncated after Asp421 and Glu391 residues was characterized in a full-length four-repeat tau background using quantitative electron microscopy methods under homogeneous nucleation conditions. Both C-terminal truncations decreased critical concentration relative to full-length tau, 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 tau filament accumulation depending on whether it precedes or follows nucleation.
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA.
authors.forename: Haishan
authors.initials: H
authors.lastname: Yin
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuret
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D020169:Caspases / Q000737:chemistry*; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational; D016875:tau Proteins
chemical_list: D001224:Aspartic Acid; D020169:Caspases; D018698:Glutamic Acid; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C054369:MAPT protein, human; D016875:tau Proteins