TY - JOUR
T1 - Photoswitchable paclitaxel-based microtubule stabilisers allow optical control over the microtubule cytoskeleton
AU - Müller-Deku, Adrian
AU - Meiring, Joyce C.M.
AU - Loy, Kristina
AU - Kraus, Yvonne
AU - Heise, Constanze
AU - Bingham, Rebekkah
AU - Jansen, Klara I.
AU - Qu, Xiaoyi
AU - Bartolini, Francesca
AU - Kapitein, Lukas C.
AU - Akhmanova, Anna
AU - Ahlfeld, Julia
AU - Trauner, Dirk
AU - Thorn-Seshold, Oliver
N1 - Funding Information:
This research was supported by funds from the German Research Foundation (DFG: SFB1032 Nanoagents for Spatiotemporal Control project B09 to D.T. and O.T.-S.; SFB TRR 152 project P24 number 239283807, Emmy Noether grant TH2231/1-1, and SPP 1926 project number 426018126 to O.T.-S.); the NIH (Grant R01GM126228 to D.T.; RO1AG050658 to F.B.); and the Thompson Family Foundation (TFFI to F.B.). We thank P.A.S. (LMU) for initial synthesis, F. Ermer and M. Borowiak (LMU) for initial MTT viability assays, H. Harz for microscopy access (LMU microscopy platform CALM), and CeNS (LMU) for support. We thank Natalia Marahori and Thomas Misgeld for valuable experimental feedback on AzTax3MP; and Maximilian Wranik, Michel Steinmetz, and the members of the Steinmetz group for work towards obtaining crystal structures of AzTaxs bound to tubulin. We are indebted to Tim Mitchison for his contributions to small molecule inhibitors in MT research.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Small molecule inhibitors are prime reagents for studies in microtubule cytoskeleton research, being applicable across a range of biological models and not requiring genetic engineering. However, traditional chemical inhibitors cannot be experimentally applied with spatiotemporal precision suiting the length and time scales inherent to microtubule-dependent cellular processes. We have synthesised photoswitchable paclitaxel-based microtubule stabilisers, whose binding is induced by photoisomerisation to their metastable state. Photoisomerising these reagents in living cells allows optical control over microtubule network integrity and dynamics, cell division and survival, with biological response on the timescale of seconds and spatial precision to the level of individual cells within a population. In primary neurons, they enable regulation of microtubule dynamics resolved to subcellular regions within individual neurites. These azobenzene-based microtubule stabilisers thus enable non-invasive, spatiotemporally precise modulation of the microtubule cytoskeleton in living cells, and promise new possibilities for studying intracellular transport, cell motility, and neuronal physiology.
AB - Small molecule inhibitors are prime reagents for studies in microtubule cytoskeleton research, being applicable across a range of biological models and not requiring genetic engineering. However, traditional chemical inhibitors cannot be experimentally applied with spatiotemporal precision suiting the length and time scales inherent to microtubule-dependent cellular processes. We have synthesised photoswitchable paclitaxel-based microtubule stabilisers, whose binding is induced by photoisomerisation to their metastable state. Photoisomerising these reagents in living cells allows optical control over microtubule network integrity and dynamics, cell division and survival, with biological response on the timescale of seconds and spatial precision to the level of individual cells within a population. In primary neurons, they enable regulation of microtubule dynamics resolved to subcellular regions within individual neurites. These azobenzene-based microtubule stabilisers thus enable non-invasive, spatiotemporally precise modulation of the microtubule cytoskeleton in living cells, and promise new possibilities for studying intracellular transport, cell motility, and neuronal physiology.
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U2 - 10.1038/s41467-020-18389-6
DO - 10.1038/s41467-020-18389-6
M3 - Article
C2 - 32934232
AN - SCOPUS:85091054212
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4640
ER -