Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment

Chung, Peter J.; Song, Chaeyeon; Deek, Joanna; Miller, Herbert C.; Li, Youli; Choi, Myung Chul; Wilson, Leslie; Feinstein, Stuart C.; Safinya, Cyrus R.

doi:10.1038/ncomms12278

Cited by 49 publications

(59 citation statements)

References 36 publications

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“…S5C and movie 9). This is consistent with recent work showing that tau binds to microtubules through its microtubule binding domains, while the intrinsically disordered N-terminal domain acts as a brush, which keep microtubules at a constant distance in microtubule bundles (Chung et al, 2016;Marx et al, 2000;Méphon-Gaspard et al, 2016;Mukhopadhyay and Hoh, 2001;Mukhopadhyay et al, 2004).…”

Section: Resultssupporting

confidence: 91%

“…In healthy brains, tau localizes to the axons of neurons while other MAPs localize to dendrites (Aronov et al, 2001;Matus, 1988). In vitro, it can stimulate the growth rate of microtubules (Drechsel et al, 1992;Kadavath et al, 2015), diffuse along and bundle microtubules (Chen et al, 1992;Chung et al, 2016;Hinrichs et al, 2012;Rosenberg et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase

Hernández-Vega

Braun

Scharrel

et al. 2017

Preprint

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Non-centrosomal microtubule bundles play important roles in cellular organization and function. Although many diverse proteins are known that can bundle microtubules, biochemical mechanisms by which cells could locally control the nucleation and formation of microtubule bundles are understudied. Here, we demonstrate that concentration of tubulin into a condensed, liquid-like compartment composed of the unstructured neuronal protein tau is sufficient to nucleate microtubule bundles. We show that under conditions of macro-molecular crowding, tau forms liquid drops. Tubulin partitions into these drops, efficiently increasing tubulin concentration and driving the nucleation of microtubules. These growing microtubules form bundles enclosed in a liquid sheath of tau. Our data suggest that condensed compartments of microtubule bundling proteins could promote the local formation of microtubule bundles in neurons by acting as non-centrosomal microtubule nucleation centers, and that liquid-like tau encapsulation could provide both stability and plasticity to long axonal microtubule bundles.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase

Hernández-Vega

Braun

Scharrel

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…6d ). Microtubules were often organized in bundles with hexagonal symmetry, similar to the tau-induced microtubule fascicles described previously 30 . To quantify this effect, the number of microtubules was determined in individual axons.…”

Section: Resultssupporting

confidence: 70%

Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects

Lathuilière

Valdés

Papin

et al. 2017

Sci Rep

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Tau pathology is associated with cognitive decline in Alzheimer’s disease, and missense tau mutations cause frontotemporal dementia. Hyperphosphorylation and misfolding of tau are considered critical steps leading to tauopathies. Here, we determine how motifs controlling conformational changes in the microtubule-binding domain determine tau pathology in vivo. Human tau was overexpressed in the adult mouse forebrain to compare variants carrying residues that modulate tau propensity to acquire a β-sheet conformation. The P301S mutation linked to frontotemporal dementia causes tau aggregation and rapidly progressing motor deficits. By comparison, wild-type tau becomes heavily hyperphosphorylated, and induces behavioral impairments that do not progress over time. However, the behavioral defects caused by wild-type tau can be suppressed when β-sheet breaking proline residues are introduced in the microtubule-binding domain of tau. This modification facilitates tau interaction with microtubules, as shown by lower levels of phosphorylation, and by the enhanced protective effects of mutated tau against the severing of the cytoskeleton in neurons exposed to vinblastine. Altogether, motifs that are critical for tau conformation determine interaction with microtubules and subsequent pathological modifications, including phosphorylation and aggregation.

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“…However, subsequent studies cast doubts on this conclusion [ 10 , 11 ]. Although the resulting controversy has not been resolved completely [ 12 , 13 ], it is now widely accepted that the observed MT bundling by classical MAPs reflects a secondary effect of MT stabilization induced by their direct binding [ 14 , 15 ]. In fact, MT-stabilizing agents, such as taxol and a non-hydrolysable GTP analog, induce MT bundling in vivo [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of the microtubule-regulating activity of microtubule crosslinking factor 1

et al. 2017

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The variety of microtubule arrays observed across different cell types should require a diverse group of proteins that control microtubule organization. Nevertheless, mainly because of the intrinsic propensity of microtubules to easily form bundles upon stabilization, only a small number of microtubule crosslinking proteins have been identified, especially in postmitotic cells. Among them is microtubule crosslinking factor 1 (MTCL1) that not only interconnects microtubules via its N-terminal microtubule-binding domain (N-MTBD), but also stabilizes microtubules via its C-terminal microtubule-binding domain (C-MTBD). Here, we comprehensively analyzed the assembly structure of MTCL1 to elucidate the molecular basis of this dual activity in microtubule regulation. Our results indicate that MTCL1 forms a parallel dimer not only through multiple homo-interactions of the central coiled-coil motifs, but also the most C-terminal non-coiled-coil region immediately downstream of the C-MTBD. Among these homo-interaction regions, the first coiled-coil motif adjacent to N-MTBD is sufficient for the MTCL1 function to crosslink microtubules without affecting the dynamic property, and disruption of this motif drastically transformed MTCL1-induced microtubule assembly from tight to network-like bundles. Notably, suppression of the homo-interaction of this motif inhibited the endogenous MTCL1 function to stabilize Golgi-associated microtubules that are essential for Golgi-ribbon formation. Because the microtubule-stabilizing activity of MTCL1 is completely attributed to C-MTBD, the present study suggests possible interplay between N-MTBD and C-MTBD, in which normal crosslinking and accumulation of microtubules by N-MTBD is essential for microtubule stabilization by C-MTBD.

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Tau mediates microtubule bundle architectures mimicking fascicles of microtubules found in the axon initial segment

Cited by 49 publications

References 36 publications

Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase

Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase

Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects

Molecular basis of the microtubule-regulating activity of microtubule crosslinking factor 1

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