The structure and phase of tau: from monomer to amyloid filament
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Cellular and Molecular Life Sciences
REVIEW
The structure and phase of tau: from monomer to amyloid filament Yifan Zeng1,2 · Jing Yang1,2 · Bailing Zhang1,2 · Meng Gao1,2 · Zhengding Su1,2 · Yongqi Huang1,2 Received: 4 July 2020 / Revised: 20 September 2020 / Accepted: 7 October 2020 © Springer Nature Switzerland AG 2020
Abstract Tau is a microtubule-associated protein involved in regulation of assembly and spatial organization of microtubule in neurons. However, in pathological conditions, tau monomers assemble into amyloid filaments characterized by the cross-β structures in a number of neurodegenerative diseases known as tauopathies. In this review, we summarize recent progression on the characterization of structures of tau monomer and filament, as well as the dynamic liquid droplet assembly. Our aim is to reveal how post-translational modifications, amino acid mutations, and interacting molecules modulate the conformational ensemble of tau monomer, and how they accelerate or inhibit tau assembly into aggregates. Structure-based aggregation inhibitor design is also discussed in the context of dynamics and heterogeneity of tau structures. Keywords Protein aggregation · Liquid–liquid phase separation · Drug design · Conformation transition · Intrinsically disordered protein
Introduction Tau protein is encoded by the MAPT gene which is located on chromosome 17. Six different tau isoforms are generated by alternative splicing, containing zero, one or two N-terminal inserts and three or four microtubule-binding repeats [1]. The constructs of 2N4R and 2N3R are illustrated in Fig. 1a. Tau protein can be divided into four distinct portions: the N-terminal domain (NTD), the proline-rich domain (PRD), the microtubule-binding domain (MTBD), and the C-terminal domain (CTD). The two aggregationprone hexapeptide motifs, PHF6* (275VQIINK280) and PHF6 (306VQIVYK311), are located on the R2 repeat and R3 repeat of MTBD, respectively. Consequently, the 4R tau isoform contains two hexapeptide motifs, and the 3R tau isoform has only one hexapeptide motif. Tau is mainly expressed in central and peripheral nerve systems, where it is largely distributed in axons. As a microtubule-associated protein, tau regulates assembly and spatial * Yongqi Huang [email protected] 1
Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China
Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China
2
organization of microtubule, thus playing a critical role in axon development and navigation (Fig. 1b) [2, 3]. Tau monomer is intrinsically disordered, with some transient secondary structure elements populated. However, tau monomers assemble into amyloid filaments characterized by the cross-β structures in a number of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD), Pick’s disease (PiD), chronic traumatic encephalopathy (CTE), and corticobasal degeneration (CBD) [4–7]. Consequently, tau protein is widely believe
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