Tau protein induces bundling of microtubules in vitro: Comparison of different tau isoforms and a tau protein fragment

Scott, Clay W.; Klika, Andrea B.; Lo, Mathew M. S.; Norris, Tyrrell E.; Caputo, Claudia B.

doi:10.1002/jnr.490330104

Cited by 66 publications

(48 citation statements)

References 56 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, these flanking regions might have a role in the organization of axonal microtubules since electron micrographs of the axon indicate that tau protein protrudes from the microtubule wall, appearing as cross-bridges between microtubules spaced 20-30 nm apart [Hirokawa et al, 1988;Chen et al, 19921. So far, no region of tau protein separate from tau's microtubulebinding domain has been identified as being required for the organization of cellular microtubules into bundles, suggesting that bundling in vivo is a consequence of microtubule stabilization by tau [Lee and Rook, 1992;Kanai et al, 19921. Bundling of microtubules in the presence of tau protein or fragments thereof has also been observed in cell-free systems [Melki et al, 1991;Scott et al, 1992;Brandt and Lee, 1993a;Lu and Wood, 19931. However, the reIation between in vitro and in vivo bundles remains unclear.…”

Section: Introductionmentioning

confidence: 97%

Orientation, assembly, and stability of microtubule bundles induced by a fragment of tau protein

Brandt

Lee

1994

Cell Motil. Cytoskeleton

View full text Add to dashboard Cite

The neuronal microtubule-associated protein tau has been implicated in the development of axonal morphology including the organization of microtubules into a uniformly oriented array of microtubules commonly referred to as "bundle." Determination of the functional organization of tau has revealed that regions of tau protein which flank the microtubule-binding domain affect the bundling of microtubules in vitro with a microtubule-binding fragment of tau being most effective [Brandt and Lee, 1993: J. Biol. Chem. 268:3414-3419]. In order to study the relation of microtubule bundles that form in vitro to those observed in the axon, we determined the orientation of individual microtubules in bundles and the effects of bundling on microtubule assembly and stability in cell-free assembly reactions. Here we report that bundles induced by a microtubule-binding fragment of tau contain randomly oriented microtubules as determined by using the difference in growth rates at microtubule plus and minus ends. We demonstrate that in vitro bundling increases microtubule growth (about 30%), stabilizes microtubules against dilution- and cold-induced disassembly, and allows microtubule nucleation despite the absence of a tau region which has previously been shown to be required for tau-dependent microtubule nucleation. We conclude that conditions that stabilize microtubules can lead to bundle formation and allow microtubule assembly by a mechanism different from that employed by microtubule-associated proteins. The data also support the view that additional mechanisms besides the action of tau and tubulin exist in order to organize microtubules in the axon.

show abstract

Section: Introductionmentioning

confidence: 97%

Orientation, assembly, and stability of microtubule bundles induced by a fragment of tau protein

Brandt

Lee

1994

Cell Motil. Cytoskeleton

View full text Add to dashboard Cite

show abstract

“…Among other functions, tau promotes the assembly of MTs into well organized, evenly spaced bundles in neuronal axons (1)(2)(3)(4)(5)(6) and regulates the growing and shortening dynamics of individual MTs (7)(8)(9)(10)(11). Tau dysfunction has long been correlated with many neurodegenerative diseases, including Alzheimer's and related dementias.…”

mentioning

confidence: 99%

Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis

Rosenberg¹,

Ross

Feinstein

et al. 2008

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

146

161

View full text Add to dashboard Cite

Tau is an intrinsically unstructured microtubule (MT)-associated protein capable of binding to and organizing MTs into evenly spaced parallel assemblies known as ''MT bundles.'' How tau achieves MT bundling is enigmatic because each tau molecule possesses only one MT-binding region. To dissect this complex behavior, we have used a surface forces apparatus to measure the interaction forces of the six CNS tau isoforms when bound to mica substrates in vitro. Two types of measurements were performed for each isoform: symmetric configuration experiments measured the interactions between two tau-coated mica surfaces, whereas ''asymmetric'' experiments examined tau-coated surfaces interacting with a smooth bare mica surface. Depending on the configuration (of which there were 12), the forces were weakly adhesive, strongly adhesive, or purely repulsive. The equilibrium spacing was determined mainly by the length of the tau projection domain, in contrast to the adhesion force/energy, which was determined by the number of repeats in the MT-binding region. Taken together, the data are incompatible with tau acting as a monomer; rather, they indicate that two tau molecules associate in an antiparallel configuration held together by an electrostatic ''zipper'' of complementary salt bridges composed of the N-terminal and central regions of each tau monomer, with the C-terminal MT-binding regions extending outward from each end of the dimeric backbone. This tau dimer determines the length and strength of the linker holding two MTs together and could be the fundamental structural unit of tau, underlying both its normal and pathological action.bridging interaction ͉ intrinsically unstructured proteins ͉ protein dimerization ͉ surface forces ͉ bioadhesion T he neural microtubule (MT)-associated protein (MAP) tau is essential for the proper development and maintenance of the nervous system. Among other functions, tau promotes the assembly of MTs into well organized, evenly spaced bundles in neuronal axons (1-6) and regulates the growing and shortening dynamics of individual MTs (7-11). Tau dysfunction has long been correlated with many neurodegenerative diseases, including Alzheimer's and related dementias. In the past decade, mutational analyses have demonstrated a direct cause-and-effect relationship between tau dysfunction and/or misregulation and the dramatic neuronal cell death underlying many of these dementias [for example,]. Some mutations cause amino acid substitutions in tau, whereas others are regulatory, causing aberrant patterns of tau RNA splicing without affecting the tau amino acid sequence.As a result of alternative RNA splicing, there are six naturally occurring isoforms of tau expressed in the CNS (Fig. 1). Based on sequence analysis and structure-function dissection (5,8,9,(15)(16)(17)(18), tau can be viewed as possessing four distinct regions. The C-terminal tail contains both basic and acidic subregions and serves to indirectly regulate tau binding to MTs, at least in part via regulated phosphorylation. On the...

show abstract

“…Differences between the short, medium, and long isoforms have been much less intensively investigated. Although these N-terminal inserts do not affect MT binding affinity (27), they do appear to regulate MT spacing and bundling (31)(32)(33)(34). However, their ability to regulate MT assembly and dynamics has not been methodically investigated.…”

mentioning

confidence: 99%

Three- and Four-repeat Tau Regulate the Dynamic Instability of Two Distinct Microtubule Subpopulations in Qualitatively Different Manners

Levy¹,

LeBoeuf²,

Massie

et al. 2005

Journal of Biological Chemistry

102

View full text Add to dashboard Cite

The microtubule-associated protein tau is implicated in the pathogenesis of many neurodegenerative diseases, including fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), in which both RNA splicing and amino acid substitution mutations in tau cause dominantly inherited early onset dementia. RNA-splicing FTDP-17 mutations alter the wildtype ϳ50:50 3-repeat (3R) to 4-repeat (4R) tau isoform ratio, usually resulting in an excess of 4R tau. To examine further how splicing mutations might cause dysfunction by misregulation of microtubule dynamics, we used video microscopy to determine the in vitro behavior of individual microtubules stabilized by varying amounts of human 4R and 3R tau. At low tau:tubulin ratios (1:55 and 1:45), all 3R isoforms reduced microtubule growth rates relative to the no-tau control, whereas all 4R isoforms increased them; however, at a high tau:tubulin ratio (1:20), both 4R and 3R tau increased the growth rates. Further analysis revealed two distinct subpopulations of growing microtubules in the absence of tau. Increasing concentrations of both 4R and 3R tau resulted in an increase in the size of the faster growing subpopulation of microtubules; however, 4R tau caused a redistribution to the faster growing subpopulation at lower tau:tubulin ratios than 3R tau. This modulation of discrete growth rate subpopulations by tau suggests that tau causes a conformational shift in the microtubule resulting in altered dynamics. Quantitative and qualitative differences observed between 4R and 3R tau are consistent with a "microtubule misregulation" model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal death and dementia.

show abstract

Tau protein induces bundling of microtubules in vitro: Comparison of different tau isoforms and a tau protein fragment

Cited by 66 publications

References 56 publications

Orientation, assembly, and stability of microtubule bundles induced by a fragment of tau protein

Orientation, assembly, and stability of microtubule bundles induced by a fragment of tau protein

Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis

Three- and Four-repeat Tau Regulate the Dynamic Instability of Two Distinct Microtubule Subpopulations in Qualitatively Different Manners

Contact Info

Product

Resources

About