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Review
. 2020 Oct 19:11:590059.
doi: 10.3389/fneur.2020.590059. eCollection 2020.

Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau

Roland Brandt  1   2   3 , Nataliya I Trushina  1 , Lidia Bakota  1
Affiliations
Review

Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau

Roland Brandt et al. Front Neurol. .

Abstract

Tau protein (MAPT) is classified as a microtubule-associated protein (MAP) and is believed to regulate the axonal microtubule arrangement. It belongs to the tau/MAP2/MAP4 family of MAPs that have a similar microtubule binding region at their carboxy-terminal half. In tauopathies, such as Alzheimer's disease, tau is distributed more in the somatodendritic compartment, where it aggregates into filamentous structures, the formation of which correlates with cognitive impairments in patients. While microtubules are the dominant interaction partners of tau under physiological conditions, tau has many additional interaction partners that can contribute to its physiological and pathological role. In particular, the amino-terminal non-microtubule binding domain (N-terminal projection region, NTR) of tau interacts with many partners that are involved in membrane organization. The NTR contains intrinsically disordered regions (IDRs) that show a strong evolutionary increase in the disorder and may have been the basis for the development of new, tau-specific interactions. In this review we discuss the functional organization of the tau protein and the special features of the tau non-microtubule binding region also in the connection with the results of Tau KO models. We consider possible physiological and pathological functions of tau's non-microtubule interactions, which could indicate that interactions mediated by tau's NTR and regulated by far-reaching functional interactions of the PRR and the extreme C-terminus of tau contribute to the pathological processes.

Keywords: Alzheimer's disease; membranes; microtubule-associated protein; tau; tauopathy.

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Figures

Figure 1
Figure 1
Schematic representation of the tau-microtubule interaction. A free molecule of tau is represented as one of the potential conformations of tau (441 aa long CNS isoform) generated as described previously (20). The different tau regions were mapped onto the model and color-coded as follows: NTR (aa 1–171)—green; PRR (aa 172–243)—light blue; MBR (aa 244–368)—blue; CTR (aa 369–441)—dark blue. The structure of the MBR binding to microtubules is based on PDB:6CVJ and PDB:6CVN structures showing interactions of first two microtubule-binding repeats of tau, R1 and R2, respectively (21). Further repeats, R3 and R4, were based on PDB:6CVN. The rest of tau molecule was artistically rendered based on the free molecule of tau. Binding to a single protofilament of a microtubule segment is depicted. α-tubulin is shown in yellow and β-tubulin in dark gray. All 3D structures are represented as surfaces and were visualized and rendered using PyMOL (www.pymol.org).
Figure 2
Figure 2
Physicochemical properties of tau and individual tau regions. (A) Isoelectric point, charge and disorder of full-length tau and the NTR, PRR, MBR, and CTR. The estimated charge at pH 7 is color-coded from acidic (red) to basic (blue). The extent of disorder is indicated as gray value. (B) Differences in frequencies of amino acids in tau and its four regions compared to the frequencies of amino acids encoded by the human genome according to (22). Overrepresented values are indicated in green, underrepresented values in orange color. Amino acids are sorted from disorder-promoting to order-promoting; disorder-promoting amino acids are underlined (23). (C) Electrostatic potential of tau and a microtubule protofilament. Electrostatic surface of tau was calculated with APBS Electrostatics Plugin (24). The electrostatic potential is color coded from red (negative) to blue (positive) at physiological pH. (D) Extent of intrinsic disorder of tau. Disorder was predicted using IUPred2A long (25). The extent of disorder was mapped onto the tau surface and indicated by white to black values as low or high disorder prediction, respectively.
Figure 3
Figure 3
Functional specialization of tau regions with respect to their molecular interactions. (A) Genes coding for interaction partners of specific tau regions. Curved lines show to which region of tau the interaction partner was mapped colored by regions, respectively. NTR (1–171), green; PRR (172–243), light blue; MBR and CTR together (244–441), blue. (B) Summary representation of GO-terms for the interaction partners, which have been mapped to the different tau regions. GO-term enrichment was performed by ClueGO plugin in Cytoscape (29, 30). Significantly enriched GO-terms (pV < 0.05) associated with Biological Processes were identified using a right-sided hypergeometric test with Bonferroni correction. GO-term fusion was used to obtain the more representative terms. GO-terms were grouped and color-coded as presented in the legend below.
Figure 4
Figure 4
GO-term representation of the individual genes coding for interaction partners that have been mapped to bind to specific regions of tau. GO-terms were color-coded according to the groups as shown in Figure 3B.
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