1. Taxanes convert regions of perturbed microtubule growth into rescue sites
- Author
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Rai, Ankit, Liu, Tianyang, Glauser, Simon, Katrukha, Eugene A, Estévez-Gallego, Juan, Rodríguez-García, Ruddi, Fang, Wei-Shuo, Díaz, J Fernando, Steinmetz, Michel O, Altmann, Karl-Heinz, Kapitein, Lukas C, Moores, Carolyn A, Akhmanova, Anna, Sub Cell Biology, Celbiologie, Sub Cell Biology, Celbiologie, European Research Council, Netherlands Organization for Scientific Research, Biotechnology and Biological Sciences Research Council (UK), Ministerio de Economía y Competitividad (España), Swiss National Science Foundation, Rai, Ankit, Liu, Tianyang, Glauser, Simon, Katrukha, Eugene A., Estévez-Gallego, Juan, Rodríguez-García, Ruddi, Díaz, José Fernando, Steinmetz, Michel O., Altmann, Karl-Heinz, Kapitein, Lukas C., Moores, Carolyn A., Akhmanova, Anna, Rai, Ankit [0000-0002-3732-3597], Liu, Tianyang [0000-0003-2598-8572], Glauser, Simon [0000-0001-5911-5820], Katrukha, Eugene A. [0000-0002-9971-3603], Estévez-Gallego, Juan [0000-0003-3889-8488], Rodríguez-García, Ruddi [0000-0001-9676-4053], Díaz, José Fernando [0000-0003-2743-3319], Steinmetz, Michel O. [0000-0001-6157-3687], Altmann, Karl-Heinz [0000-0002-0747-9734], Kapitein, Lukas C. [0000-0001-9418-6739], Moores, Carolyn A. [0000-0001-5686-6290], and Akhmanova, Anna [0000-0002-9048-8614]
- Subjects
Drug development ,02 engineering and technology ,Epothilone ,010402 general chemistry ,Microtubules ,01 natural sciences ,Fluorescence imaging ,Cryoelectron microscopy ,Tubulin ,Microtubule ,Taverne ,medicine ,Humans ,General Materials Science ,Total internal reflection microscopy ,Biological sciences ,Cytoskeleton ,Taxane ,biology ,Chemistry ,Mechanical Engineering ,General Chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,0104 chemical sciences ,Kinetics ,Mechanics of Materials ,biology.protein ,Biophysics ,Taxoids ,0210 nano-technology ,HeLa Cells ,medicine.drug - Abstract
15 p.-6 fig., Microtubules are polymers of tubulin dimers, and conformational transitions in the microtubule lattice drive microtubule dynamic instability and affect various aspects of microtubule function. The exact nature of these transitions and their modulation by anticancer drugs such as Taxol and epothilone, which can stabilize microtubules but also perturb their growth, are poorly understood. Here, we directly visualize the action of fluorescent Taxol and epothilone derivatives and show that microtubules can transition to a state that triggers cooperative drug binding to form regions with altered lattice conformation. Such regions emerge at growing microtubule ends that are in a pre-catastrophe state, and inhibit microtubule growth and shortening. Electron microscopy and in vitro dynamics data indicate that taxane accumulation zones represent incomplete tubes that can persist, incorporate tubulin dimers and repeatedly induce microtubule rescues. Thus, taxanes modulate the material properties of microtubules by converting destabilized growing microtubule ends into regions resistant to depolymerization., This work was supported by the European Research Council Synergy (grant no. 609822) and the Netherlands Organization for Scientific Research CW ECHO (grant no. 711.015.005 to A.A.), by a Biotechnology and Biological Sciences Research Council grant (no. BB/N018176/1 to C.A.M.), by an EMBO Long Term Fellowship to R.R.-G., by the CAMS Innovation Fund for Medical Sciences (grant no. 2016-I2M-1-010 to W.-S.F.), by grants from MINECO/FEDER (no. BFU2016-75319-R to J.F.D.) and by COST Action (no. CM1407 to J.F.D. and K.-H.A.). M.O.S is supported by a grant from the Swiss National Science Foundation (no. 31003A_166608).
- Published
- 2019