Abstract
Tau proteins regulate the dynamics, stability and transport properties of cytoskeletal scaffolding microtubules. Functional tau monomer has been classified as an intrinsically disordered protein. However, the degree of foldedness of the protein and intrinsic capability of the protein to gain rigidity is not well understood yet. We employed fluorescence, circular dichroism (CD), and Fourier transform infrared (FTIR) spectroscopic techniques to analysis the foldedness of the hTau24 isoform.Fluorescence data with bis-ANS reveals that in acidic buffer (pH 3.3), the protein contains predominantly a molten globular structure, while the rigidity degrees partially collapse to a pre molten globular state in neutral and alkaline buffers. Exploiting the tyrosine fluorescence at similar solvent conditions suggests a three-dimensional structured domain(s) exists in soluble tau. Under modest solvent changes, the soluble protein can adopt higher β-turn content, and extended/β-sheet structures compared to the dominant disordered structure of soluble tau in neutral buffer. Our CD data did not reveal the presence of extended helix polyproline II structure.In conclusion, due to the flexibility and potential ability of soluble tau to gain or lose rigidity, microtubule-binding interactions that occur through specific folding is certainly a strong possibility. Furthermore, regardless of the oligomerization behavior of tau, it is feasible that loss of foldedness and increased rigidity of the secondary structure content of soluble protein may contribute to a loss-of-function and eventually causes cytotoxicity, independent of intramolecular association.
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