期刊
MOLECULAR BIOLOGY OF THE CELL
卷 29, 期 2, 页码 154-165出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E17-06-0429
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资金
- CNRS/INSERM ATIP-Avenir program
- Agence Nationale pour la Recherche [ANR-2011-MALZ-001-02]
- Union France Alzheimer et Maladies Apparentees
- Federation pour la Recherche sur le Cerveau (FRC) [AAP SM 2015]
- Ministere de l'Enseignement Superieur et de la Recherche
- Fondation pour la Recherche Medicale [FDT20160435467, FDT20140930826]
- Rhone-Alpes region (Program Cible 2011'')
- Grenoble Instruct Center (ISBG) [UMS 3518 CNRS-CEA-UJF-EMBL]
- FRISBI [ANR-10-INSB-05-02]
- GRAL within the Grenoble Partnership for Structural Biology (PSB) [ANR-10LABX- 49-01]
- RhoneAlpes region
- Fonds Feder
- Fondation pour la Recherche Medicale
In neurons, microtubule networks alternate between single filaments and bundled arrays under the influence of effectors controlling their dynamics and organization. Tau is a microtubule bundler that stabilizes microtubules by stimulating growth and inhibiting shrinkage. The mechanisms by which tau organizes microtubule networks remain poorly understood. Here, we studied the self-organization of microtubules growing in the presence of tau isoforms and mutants. The results show that tau's ability to induce stable microtubule bundles requires two hexapeptides located in its microtubule-binding domain and is modulated by its projection domain. Site-specific pseudophosphorylation of tau promotes distinct microtubule organizations: stable single microtubules, stable bundles, or dynamic bundles. Disease-related tau mutations increase the formation of highly dynamic bundles. Finally, cryo-electron microscopy experiments indicate that tau and its variants similarly change the microtubule lattice structure by increasing both the protofilament number and lattice defects. Overall, our results uncover novel phosphodependent mechanisms governing tau's ability to trigger microtubule organization and reveal that disease-related modifications of tau promote specific microtubule organizations that may have a deleterious impact during neurodegeneration.
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