Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro
Department of Cell Biology
Alternative Splicing; Amino Acid Sequence; Humans; Molecular Sequence Data; *Protein Folding; Protein Isoforms; tau Proteins
Alzheimer's disease and other tauopathies are characterized by the intracellular accumulation of insoluble filaments of the microtubule-associated protein tau. The six canonical tau isoforms in the adult brain consist of an N-terminal "projection" domain followed by a proline-rich region, a microtubule-binding repeat region, and a C-terminal tail. However, alternative splicing in exon 6 produces an additional set of tau isoforms, termed 6D and 6P, which contain only the N-terminus and part of the proline-rich region. We have previously shown that constructs representing N-terminal fragments of tau, which resemble the naturally occurring 6P and 6D isoforms, inhibit polymerization of the full-length protein in an in vitro filament formation assay and traced the inhibitory activity to amino acids 18-42. Here we report that 6P and 6D tau isoforms inhibit polymerization of full-length tau (hTau40) in a similar manner, likely by stabilizing full-length tau in a soluble conformation. The absence of exons 2 and 3 decreased the effectiveness of the 6D isoforms but not the 6P variants or the N-terminal tau fragments from our previous study, indicating that the 18-42 region is not the sole determinant of inhibitory ability. Finally, this paper demonstrates that inhibition is blocked by pseudophosphorylation of tyrosines 18 and 29, providing a potential link between tyrosine phosphorylation and disease progression. Taken together, these results indicate that the 6P/6D isoforms are potential endogenous inhibitors of tau filament formation and suggest a mechanism by which this ability may be disrupted in disease.
DOI of Published Version
Biochemistry. 2009 Dec 29;48(51):12290-7. Link to article on publisher's site
Lapointe NE, Horowitz PM, Guillozet-Bongaarts AL, Silva A, Andreadis A, Binder LI. (2009). Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro. Andreadis Lab Publications. https://doi.org/10.1021/bi901304u. Retrieved from https://escholarship.umassmed.edu/andreadis/3