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1
Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner

Choi, Myung Chul,Chung, Peter J.,Song, Chaeyeon,Miller, Herbert P.,Kiris, E.,Li, Youli,Wilson, Leslie,Feinstein, Stuart C.,Safinya, Cyrus R. Elsevier 2017 Biochimica et biophysica acta, General subjects Vol.1861 No.1
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Abstract Background Microtubules (MTs) are protein nanotubes comprised of straight protofilaments (PFs), head to tail assemblies of αβ-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 ΦTau at paclitaxel/tubulin-dimer molar ratio ΛPtxl =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≤ΛPtxl ≤1/4) and Tau (human isoform 3RS, 0≤Φ3RS ≤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 ΛPtxl =1/1 where microtubule bundles are absent, in the lower paclitaxel concentration regime (ΛPtxl ≤1/4), we observe both microtubule doublets and triplets with increasing Tau. Furthermore, increasing paclitaxel concentration (up to ΛPtxl =1/1) slightly decreased the average microtubule diameter (by ~1 PF) while increasing Tau concentration (up to Φ3RS =1/2) significantly increased the diameter (by ~2–3 PFs). Conclusions The suppression of Tau-mediated microtubule bundling with increasing paclitaxel is consistent with paclitaxel 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. Highlights <UL> <LI> Increasing paclitaxel suppresses Tau-mediated microtubule bundling. </LI> <LI> A length-dependent mechanism for Tau-mediated microtubule bundling is proposed. </LI> <LI> Understanding MAP/microtubule behavior requires elimination of paclitaxel use. </LI> </UL>
2
Human Microtubule-Associated-Protein Tau Regulates the Number of Protofilaments in Microtubules: A Synchrotron X-Ray Scattering Study

Choi, M.C.,Raviv, U.,Miller, H.P.,Gaylord, M.R.,Kiris, E.,Ventimiglia, D.,Needleman, D.J.,Kim, M.W.,Wilson, L.,Feinstein, S.C.,Safinya, C.R. Biophysical Society ; Published for the Biophysica 2009 Biophysical journal Vol.97 No.2
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Microtubules (MTs), a major component of the eukaryotic cytoskeleton, are 25 nm protein nanotubes with walls comprised of assembled protofilaments built from αβ heterodimeric tubulin. In neural cells, different isoforms of the microtubule-associated-protein (MAP) tau regulate tubulin assembly and MT stability. Using synchrotron small angle x-ray scattering (SAXS), we have examined the effects of all six naturally occurring central nervous system tau isoforms on the assembly structure of taxol-stabilized MTs. Most notably, we found that tau regulates the distribution of protofilament numbers in MTs as reflected in the observed increase in the average radius <RMT> of MTs with increasing Φ, the tau/tubulin-dimer molar ratio. Within experimental scatter, the change in <RMT> seems to be isoform independent. Significantly, <RMT> was observed to rapidly increase for 0 < Φ < 0.2 and saturate for Φ between 0.2-0.5. Thus, a local shape distortion of the tubulin dimer on tau binding, at coverages much less than a monolayer, is spread collectively over many dimers on the scale of protofilaments. This implies that tau regulates the shape of protofilaments and thus the spontaneous curvature CoMT of MTs leading to changes in the curvature CMT (=1/RMT). An important biological implication of these findings is a possible allosteric role for tau where the tau-induced shape changes of the MT surface may effect the MT binding activity of other MAPs present in neurons. Furthermore, the results, which provide insight into the regulation of the elastic properties of MTs by tau, may also impact biomaterials applications requiring radial size-controlled nanotubes.
3
Development of Gradient Centrifugal Partition Chromatography Method and Its Application for the Isolation of 3,5-Dimethoxyphenanthrene-2,7-diol and Batatasin-I from Dioscorea opposita

Kee Dong Yoon,양민혜,Young-Won Chin,Yoenjun Kim,Hye Ryung Kim,Kiri Choi,Ju Hyun Park,김진웅 한국생약학회 2009 Natural Product Sciences Vol.15 No.3
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Gradient centrifugal partition chromatography (GCPC) method was developed and applied to isolate 3,5-dimethoxyphenanthrene-2,7-diol (DMP) and batatasin-I (BA-I) from the dichloromethane soluble extract of Dioscorea opposita. In this method, the lower phase of n-hexane-methanol-water system (HMW, 10 : 9 : 1, v/v) was used as a mobile phase A (MpA) and water was used as a mobile phase B (MpB). This gradient CPC method is comparable to that of reversed-phase HPLC method in that the stationary upper-phase of HMW (10 : 9 : 1 v/v) works as if it were reversed-phase silica gel due to its hydrophobic property, while the lower phase (MpA) and water (MpB) functioned as hydrophilic mobile phases. The initial condition of the mobile phase was 20% MpA/ 80% MpB and maintained for 150 min to obtain DMP (1.2 mg), and then MpA was increased up to 50% to elute BA-I (1.7 mg). The purities of DMP and BA-I were 94.1% and 98.3% with the recovery yields of 83% and 86%, respectively. Similar results were obtained by linear-gradient CPC. The CPC peak fractions were identified by comparing their retention time to those of authentic samples of DMP and BA-I and their spectroscopic data (1H NMR and 13C NMR) to those of literature values.