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Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding.

ABSTRACT: Opposing views have been proposed regarding the role of tau, the principal microtubule-associated protein in axons. On the one hand, tau forms cross-bridges at the interface between microtubules and induces microtubule bundling in neurons. On the other hand, tau is also considered a polymer brush which efficiently separates microtubules. In mature axons, microtubules are indeed arranged in parallel arrays and are well separated from each other. To reconcile these views, we developed a mechanistic model based on in vitro and cellular approaches combined to analytical and numerical analyses. The results indicate that tau forms long-range cross-bridges between microtubules under macromolecular crowding conditions. Tau cross-bridges prevent the redistribution of tau away from the interface between microtubules, which would have occurred in the polymer brush model. Consequently, the short-range attractive force between microtubules induced by macromolecular crowding is avoided and thus microtubules remain well separated from each other. Interestingly, in this unified model, tau diffusion on microtubules enables to keep microtubules evenly distributed in axonal sections at low tau levels.

SUBMITTER: Mephon-Gaspard A

PROVIDER: S-EPMC5002045 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding.

Méphon-Gaspard Alix A Boca Mirela M Pioche-Durieu Catherine C Desforges Bénédicte B Burgo Andrea A Hamon Loic L Piétrement Olivier O Pastré David D

Cellular and molecular life sciences : CMLS 20160413 19

Opposing views have been proposed regarding the role of tau, the principal microtubule-associated protein in axons. On the one hand, tau forms cross-bridges at the interface between microtubules and induces microtubule bundling in neurons. On the other hand, tau is also considered a polymer brush which efficiently separates microtubules. In mature axons, microtubules are indeed arranged in parallel arrays and are well separated from each other. To reconcile these views, we developed a mechanisti ...[more]

PMID: 27076215

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Project description:Background. A large proportion of natural grasslands around the world is exposed to overgrazing resulting in land degradation and biodiversity loss. Although there is an increasing effort in the promotion of sustainable livestock management, rangeland degradation still occurs because animals' foraging behaviour is highly selective at different spatial scales. The assessment of the ecological mechanisms modulating the spatial distribution of grazing and how to control it has critical implications for long term conservation of resources and the sustainability of livestock production. Considering the relevance of social interactions on animals' space use patterns, our aim was to explore the potential effects of including animals' social context into management strategies using domestic sheep grazing in rangelands as case study. Methods. We used GPS data from 19 Merino sheep (approximately 10% of the flock) grazing on three different paddocks (with sizes from 80 to 1000 Ha) during a year, to estimate resource selection functions of sheep grazing in flocks of different levels of heterogeneity. We assessed the effects of sheep class (i.e., ewes, wethers, and hoggets), age, body condition and time since release on habitat selection patterns. Results. We found that social rank was reflected on sheep habitat use, where dominant individuals (i.e., reproductive females) used more intensively the most preferred areas and low-ranked (i.e., yearlings) used less preferred areas. Our results showed that when sheep grazed on more heterogeneous flocks, grazing patterns were more evenly distributed at all the paddocks considered in this study. On the other hand, when high-ranked individuals were removed from the flock, low-ranked sheep shifted their selection patterns by increasing the use of the most preferred areas and strongly avoided to use less preferred sites (i.e., a highly selective grazing behaviour). Discussion. Although homogenization and segregation of flocks by classes are common practices to increase flock productivity, we are proposing an alternative that employs behavioural interactions in heterogeneous flocks to generate more evenly distributed grazing patterns. This practice can be combined with other practices such as rotational grazing and guardian dogs (to decrease mortality levels that may be generated by sheep grazing on more risky habitats). This does not imply any modifications of livestock stocking rates and densities or any additional investments for labour and materials. Considering livestock behaviour is critical for the design of sustainable management practices that balance landscape conservation and livestock productivity.

Project description:Many protein functions can be directly linked to conformational changes. Inside cells, the equilibria and transition rates between different conformations may be affected by macromolecular crowding. We have recently developed a new approach for modeling crowding effects, which enables an atomistic representation of "test" proteins. Here this approach is applied to study how crowding affects the equilibria and transition rates between open and closed conformations of seven proteins: yeast protein disulfide isomerase (yPDI), adenylate kinase (AdK), orotidine phosphate decarboxylase (ODCase), Trp repressor (TrpR), hemoglobin, DNA beta-glucosyltransferase, and Ap(4)A hydrolase. For each protein, molecular dynamics simulations of the open and closed states are separately run. Representative open and closed conformations are then used to calculate the crowding-induced changes in chemical potential for the two states. The difference in chemical-potential change between the two states finally predicts the effects of crowding on the population ratio of the two states. Crowding is found to reduce the open population to various extents. In the presence of crowders with a 15 A radius and occupying 35% of volume, the open-to-closed population ratios of yPDI, AdK, ODCase and TrpR are reduced by 79%, 78%, 62% and 55%, respectively. The reductions for the remaining three proteins are 20-44%. As expected, the four proteins experiencing the stronger crowding effects are those with larger conformational changes between open and closed states (e.g., as measured by the change in radius of gyration). Larger proteins also tend to experience stronger crowding effects than smaller ones [e.g., comparing yPDI (480 residues) and TrpR (98 residues)]. The potentials of mean force along the open-closed reaction coordinate of apo and ligand-bound ODCase are altered by crowding, suggesting that transition rates are also affected. These quantitative results and qualitative trends will serve as valuable guides for expected crowding effects on protein conformation changes inside cells.

Dataset Information

Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding.

Publications

Role of tau in the spatial organization of axonal microtubules: keeping parallel microtubules evenly distributed despite macromolecular crowding.

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