Liquid–liquid phase separation of tau: From molecular biophysics to physiology and disease

Abstract

Biomolecular condensation via liquid–liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs), with and without nucleic acids, has drawn widespread interest due to the rapidly unfolding role of phase‐separated condensates in a diverse range of cellular functions and human diseases. Biomolecular condensates form via transient and multivalent intermolecular forces that sequester proteins and nucleic acids into liquid‐like membrane‐less compartments. However, aberrant phase transitions into gel‐like or solid‐like aggregates might play an important role in neurodegenerative and other diseases. Tau, a microtubule‐associated neuronal IDP, is involved in microtubule stabilization, regulates axonal outgrowth and transport in neurons. A growing body of evidence indicates that tau can accomplish some of its cellular activities via LLPS. However, liquid‐to‐solid transition resulting in the abnormal aggregation of tau is associated with neurodegenerative diseases. The physical chemistry of tau is crucial for governing its propensity for biomolecular condensation which is governed by various intermolecular and intramolecular interactions leading to simple one‐component and complex multi‐component condensates. In this review, we aim at capturing the current scientific state in unveiling the intriguing molecular mechanism of phase separation of tau. We particularly focus on the amalgamation of existing and emerging biophysical tools that offer unique spatiotemporal resolutions on a wide range of length‐ and time‐scales. We also discuss the link between quantitative biophysical measurements and novel biological insights into biomolecular condensation of tau. We believe that this account will provide a broad and multidisciplinary view of phase separation of tau and its association with physiology and disease.

14-3-3 Proteins are Potential Regulators of Liquid–Liquid Phase Separation

“…Recently, it was found that LLPS is an intrinsic property of tau and may be involved in its function and aggregation [149][150][151][152][153]. For example, tau droplets can concentrate tubulin and nucleate microtubule bundles as well as regulate the activity of microtubule-severing enzymes and the movement of molecular motors [154,155].…”

Salt Induced Transitions in the Conformational Ensembles of Intrinsically Disordered Proteins

“…In the low [ salt ] regime ([ salt ] ≲ 200 mM), polyelectrolyte-like IDPs such as prothymosin- α and sic1 are highly expanded due to electrostatic repulsion. Therefore, oppositely charged molecules such as RNA, 95–97 DNA, polylysine, or polyarginine are required to induce LLPS through a network of heterotypic interactions between the IDPs and ligands. 98–100 Conversely, polyampholyte-like IDPs such as ERMTADn and IN are stabilized due to attractive intramolecular electrostatic interactions between positively and negatively charged residues.…”

“…In the low [salt] regime ([salt] ≲ 200 mM), polyelectrolyte-like IDPs such as prothymosinα and sic1 are highly expanded due to electrostatic repulsion. Therefore, oppositely charged molecules such as RNA, [95][96][97] DNA, polylysine, or polyarginine are required to induce LLPS through a network of heterotypic interactions between the IDPs and ligands. In the intermediate salt concentration regime (200 mM ≲ [salt] ≲ 2 M), 89,90 the electrostatic interactions are screened out, and LLPS is not observed for both polyelectrolytes and polyampholyte like IDPs (Fig.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Physiological tau droplets support important biological functions specific to the cellular compartments where they are formed [ 637 , 638 ], such as myelination [ 639 , 640 ], axonal transport [ 639 , 641 ], motor function [ 642 ], learning and memory [ 643 ], neuronal excitability [ 644 ], as well as glucose metabolism [ 645 , 646 , 647 ], DNA protection [ 648 ], and gene transcription [ 520 ]. In neurons, phase-separated tau droplets enhance the nucleation of MTs, promoting tubulin polymerization by decreasing critical concentration [ 649 , 650 ]. Physiological tau condensates not only stabilize dynamically unstable MTs [ 651 ], but can form islands on the surfaces of MTs, protecting them from severing enzymes [ 652 , 653 ].…”