Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner

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Background: Microtubules (MTs) are protein nanotubes comprised of straight protofilaments (PFs), head to tail assemblies of alpha beta-tubulin heterodimers. Previously, it was shown that Tau, a microtubule-associated protein (MAP) localized to neuronal axons, regulates the average number of PFs in microtubules with increasing inner radius <R-in(MT)> observed for increasing Tau/tubulin-dimer molar ratio Phi(Tau) at paclitaxel/tubulin-dimer molar ratio Lambda(ptxl) = 1/1. Methods: We report a synchrotron SAXS and TEM study of the phase behavior of microtubules as a function of varying concentrations of paclitaxel (1/32 <= Lambda(ptxl) <= 1/4) and Tau (human isoform 3RS, 0 <= Phi(3Rs) <= 1/2) at room temperature. Results: Tau and paclitaxel have opposing regulatory effects on microtubule bundling architectures and microtubule diameter. Surprisingly and in contrast to previous results at Air = 1/1 where microtubule bundles are absent, in the lower paclitaxel concentration regime (Lambda(ptxl) <= 1/4), we observe both microtubule doublets and triplets with increasing Tau. Furthermore, increasing paditaxel concentration (up to Lambda(ptxl) = 1/1) slightly decreased the average microtubule diameter (by similar to 1 PF) while increasing Tau concentration (up to Phi(3RS) = 1/2) significantly increased the diameter (by similar to 2-3 PFs). Conclusions: The suppression of Tau-mediated microtubule bundling with increasing paclitaxel is consistent with paditaxel seeding more, but shorter, microtubules by rapidly exhausting tubulin available for polymerization. Microtubule bundles require the aggregate Tau-Tau attractions along the microtubule length to overcome individual microtubule thermal energies disrupting bundles. General significance: Investigating MAP-mediated interactions between microtubules (as it relates to in vivo behavior) requires the elimination or minimization of paclitaxel. (C) 2016 Elsevier B.V. All rights reserved.
Publisher
ELSEVIER SCIENCE BV
Issue Date
2017-01
Language
English
Article Type
Article
Keywords

X-RAY-SCATTERING; FORMATION IN-VITRO; THERMAL FLUCTUATIONS; DYNAMIC INSTABILITY; PROTEIN-TAU; TUBULIN; TAXOL; PROTOFILAMENTS; BINDING; DOMAINS

Citation

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v.1861, no.1, pp.3456 - 3463

ISSN
0304-4165
DOI
10.1016/j.bbagen.2016.09.011
URI
http://hdl.handle.net/10203/218286
Appears in Collection
BiS-Journal Papers(저널논문)
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