Tau stabilizes microtubules by binding at the interface between tubulin heterodimers

Kadavath, Harindranath; Hofele, Romina V.; Biernat, Jacek; Kumar, Satish; Tepper, Katharina; Urlaub, Henning; Mandelkow, Eckhard; Zweckstetter, Markus

doi:10.1073/pnas.1504081112

Cited by 441 publications

(393 citation statements)

References 56 publications

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“…S4). Our observation supports NMR studies, which suggest that the N terminus retains high flexibility in the taumicrotubule complex (33,35). We find key differences between the heparin-and tubulin-bound tau conformations as well, showing that, although the binding sites for heparin and tubulin or microtubules may be the same (40), the conformational changes on binding are not simply the result of tau binding to anionic molecules or surfaces but are distinct conformational differences between the aggregation-prone and functional forms of tau.…”

Section: Discussionsupporting

confidence: 89%

“…On the surface, this observation seems contradictory. However, it has been proposed that tau's interaction with microtubules is mediated by an array of short motifs within the MTBR, with flanking residues remaining flexible (33). If a similar model holds for tau bound to multiple tubulin dimers, then we can rationalize that binding to tubulin may cause local expansion in regions involved directly in binding, whereas the flexibility of the flanking regions allows the overall dimensions of the MTBR to be maintained.…”

Section: Discussionmentioning

confidence: 94%

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A functional role for intrinsic disorder in the tau-tubulin complex

Melo

Coraor

Alpha-Cobb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tau is an intrinsically disordered protein with an important role in maintaining the dynamic instability of neuronal microtubules. Despite intensive study, a detailed understanding of the functional mechanism of tau is lacking. Here, we address this deficiency by using intramolecular single-molecule Förster Resonance Energy Transfer (smFRET) to characterize the conformational ensemble of tau bound to soluble tubulin heterodimers.Tau adopts an open conformation on binding tubulin, in which the long-range contacts between both termini and the microtubule binding region that characterize its compact solution structure are diminished. Moreover, the individual repeats within the microtubule binding region that directly interface with tubulin expand to accommodate tubulin binding, despite a lack of extension in the overall dimensions of this region. These results suggest that the disordered nature of tau provides the significant flexibility required to allow for local changes in conformation while preserving global features. The tubulin-associated conformational ensemble is distinct from its aggregation-prone one, highlighting differences between functional and dysfunctional states of tau. Using constraints derived from our measurements, we construct a model of tubulin-bound tau, which draws attention to the importance of the role of tau's conformational plasticity in function.single-molecule FRET | intrinsically disordered proteins | microtubuleassociated protein | tauopathies | Alzheimer's disease

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 94%

A functional role for intrinsic disorder in the tau-tubulin complex

Melo

Coraor

Alpha-Cobb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This increase in the ensemble-averaged inner radius of MTs, <R in MT >, indicated that MT-associated protein Tau isoforms do not just bind and stabilize MTs, for example, by enhancing PF-PF interactions but also, change the shape of αβ-tubulin and thus, PFs, leading to a change in curvature of MTs. This conclusion is consistent with recent NMR work showing that Tau binds, at least in part, between tubulin heterodimers (31).…”

Section: Significancesupporting

confidence: 93%

“…1A, Left). Although Tau strongly binds to the MT surface (∼1-3 μM affinity) (10,26), recent work suggests that Tau-MT interactions are highly dynamic and that Tau can assume numerous structures (30,31).…”

Section: Significancementioning

confidence: 99%

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Chung

Choi

Miller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer's. Here, we report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (P). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; Φ Tau = 1/ 10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to P B ∼ 10,000-20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (P B ∼ 1,000-2,000 Pa) over the same range. Remarkably, the abrupt increase in P B observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < Φ Tau < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT-MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment.Tau | intrinsically disordered proteins | microtubule | SAXS | force measurement

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“…With the ease of yeast genetics, both problems may be overcome. The failure of tau to bind to yeast tubulin is most likely due to sequence differences between yeast α-tubulin and its mammalian homolog, located at the proposed tau-binding site [102]. It may thus be possible to produce chimeric yeast/human microtubules in such a strain which can be employed for in vivo binding assays.…”

Section: Genetic Screens In Yeast -The Past the Present And The Futurementioning

confidence: 99%

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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Tau stabilizes microtubules by binding at the interface between tubulin heterodimers

Cited by 441 publications

References 56 publications

A functional role for intrinsic disorder in the tau-tubulin complex

A functional role for intrinsic disorder in the tau-tubulin complex

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

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