Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

Yanxian Lin; Yann Fichou; Andrew P Longhini; Luana C Llanes; Pengyi Yin; Guillermo C Bazan; Kenneth S Kosik; Songi Han

doi:10.1016/j.jmb.2020.166731

Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

J Mol Biol. 2021 Jan 22;433(2):166731. doi: 10.1016/j.jmb.2020.166731. Epub 2020 Dec 3.

Authors

Yanxian Lin¹, Yann Fichou², Andrew P Longhini³, Luana C Llanes⁴, Pengyi Yin², Guillermo C Bazan⁵, Kenneth S Kosik⁶, Songi Han⁷

Affiliations

¹ Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106, United States.
² Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States.
³ Molecular, Cell and Developmental Biology, University of California, Santa Barbara, CA 93106, United States.
⁴ Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States; Center for Polymers and Organic Solids, University of California, Santa Barbara, CA 93106, United States.
⁵ Departments of Chemistry and Chemical Engineering, National University of Singapore, 117543, Singapore.
⁶ Molecular, Cell and Developmental Biology, University of California, Santa Barbara, CA 93106, United States; Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, United States.
⁷ Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States; Department of Chemical Engineering, University of California, Santa Barbara, CA 93106, United States. Electronic address: [email protected].

Abstract

Amyloid aggregation of tau protein is implicated in neurodegenerative diseases, yet its facilitating factors are poorly understood. Recently, tau has been shown to undergo liquid liquid phase separation (LLPS) both in vivo and in vitro. LLPS was shown to facilitate tau amyloid aggregation in certain cases, while being independent of aggregation in other cases. It is therefore important to understand the differentiating properties that resolve this apparent conflict. We report on a model system of hydrophobically driven LLPS induced by high salt concentration (LLPS-HS), and compare it to electrostatically driven LLPS represented by tau-RNA/heparin complex coacervation (LLPS-ED). We show that LLPS-HS promotes tau protein dehydration, undergoes maturation and directly leads to canonical tau fibrils, while LLPS-ED is reversible, remains hydrated and does not promote amyloid aggregation. We show that the nature of the interaction driving tau condensation is a differentiating factor between aggregation-prone and aggregation-independent LLPS.

Keywords: amyloid aggregation; electron paramagnetic resonance; hydrophobic interaction; liquid–liquid phase separation; tau.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amyloid / chemistry*
Amyloid / metabolism
Amyloid / ultrastructure
Humans
Hydrophobic and Hydrophilic Interactions*
Liquid-Liquid Extraction* / methods
Protein Aggregates
Protein Aggregation, Pathological
Spectrum Analysis
tau Proteins / chemistry*
tau Proteins / isolation & purification*
tau Proteins / metabolism

Substances

Amyloid
Protein Aggregates
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding