Jul 26, 2019

Residue-specific identification of phase separation hot spots of Alzheimer's-related protein tau

Chemical Science
Susmitha AmbadipudiMarkus Zweckstetter


Liquid-liquid phase separation (LLPS) of proteins enables the formation of non-membrane-bound organelles in cells and is associated with cancer and neurodegeneration. Little is known however about the structure and dynamics of proteins in LLPS conditions, because of the polymorphic nature of liquid-like protein droplets. Using carbon-detected NMR experiments we here show that the conversion of the aggregation-prone repeat region of the Alzheimer's-related protein tau from the dispersed monomeric state to phase-separated liquid-like droplets involves tau's aggregation-prone hexapeptides and regulatory KXGS motifs. Droplet dissolution in presence of 1,6-hexanediol revealed that chemical shift perturbations in the hexapeptide motifs are temperature driven, while those in KXGS motifs report on phase separation. Residue-specific secondary structure analysis further indicated that tau's repeat region exists in extended conformation in the dispersed state and attains transient β-hairpin propensity upon LLPS. Taken together our work shows that NMR spectroscopy can provide high-resolution insights into LLPS-induced changes in intrinsically disordered proteins.

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Mentioned in this Paper

Gene Polymorphism
Nerve Degeneration
Hairpin Loop Sequence
Hexamethylene glycol
Protein Aggregation, Pathological
Tau Proteins
Protein Domain
Microtubule-Associated Protein Tau

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