Issue 26, 2019

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

Abstract

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
29 Jan 2019
Accepted
22 May 2019
First published
22 May 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 6503-6507

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

S. Ambadipudi, J. G. Reddy, J. Biernat, E. Mandelkow and M. Zweckstetter, Chem. Sci., 2019, 10, 6503 DOI: 10.1039/C9SC00531E

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