STRUCTURAL PLASTICITY ALLOWS DOUBLECORTIN AND DRUG-STABILIZED MICROTUBULES TO ACCOMMODATE EACH OTHER
- 1ISMB, Birkbeck College London
Abstract
Microtubule architecture and dynamics are modulated by small molecules, but how these compounds alter lattice properties and interactions with cellular regulators remains incompletely understood. We used the neuronal microtubule-associated protein doublecortin (DCX), previously reported to preferentially recognize 13-protofilament microtubules, to probe lattices stabilized by different taxanes, including the fluorescent taxane Fchitax-3. We show that DCX binds 15-protofilament Fchitax-3-stabilized microtubules, demonstrating that DCX is not a specific marker of 13-protofilament architecture. Cryo-electron microscopy revealed that the fluorescent moiety of Fchitax-3 inserts into inter-protofilament lateral contacts, explaining its effects on microtubule architecture and dynamics. DCX binds Fchitax-3 microtubules through its N-terminal DC domain, which accommodates the narrower inter-protofilament binding site in the 15-protofilament lattice. Remarkably, although Fchitax-3 induces the longitudinal lattice expansion characteristic of taxanes, DCX remodels its binding site towards its preferred compacted configuration. Thus, taxanes can modify microtubule structure in distinct ways while preserving lattice plasticity and the capacity to undergo conformational remodelling by microtubule-associated proteins. This contrasts with the comparatively rigid lattice of GMPCPP-stabilized microtubules. Consequently, interpretations of microtubule lattice states based on comparisons between taxane- and GMPCPP-stabilized microtubules may conflate structural differences with different degrees of lattice plasticity. Our findings establish the microtubule lattice as a malleable structural substrate whose drug-induced conformations can be further remodelled by cellular binding partners.
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BibTeX
@misc{ramaswamy2026structural,
title = {{STRUCTURAL PLASTICITY ALLOWS DOUBLECORTIN AND DRUG-STABILIZED MICROTUBULES TO ACCOMMODATE EACH OTHER}},
author = {V. Ramaswamy and S. W. Manka and D. D. Sharma and A. Akhmanova and A. Rai and C. Moores},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763982},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763982v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - STRUCTURAL PLASTICITY ALLOWS DOUBLECORTIN AND DRUG-STABILIZED MICROTUBULES TO ACCOMMODATE EACH OTHER
AU - V. Ramaswamy
AU - S. W. Manka
AU - D. D. Sharma
AU - A. Akhmanova
AU - A. Rai
AU - C. Moores
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763982
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763982v1
AB - Microtubule architecture and dynamics are modulated by small molecules, but how these compounds alter lattice properties and interactions with cellular regulators remains incompletely understood. We used the neuronal microtubule-associated protein doublecortin (DCX), previously reported to preferentially recognize 13-protofilament microtubules, to probe lattices stabilized by different taxanes, including the fluorescent taxane Fchitax-3. We show that DCX binds 15-protofilament Fchitax-3-stabilized microtubules, demonstrating that DCX is not a specific marker of 13-protofilament architecture. Cryo-electron microscopy revealed that the fluorescent moiety of Fchitax-3 inserts into inter-protofilament lateral contacts, explaining its effects on microtubule architecture and dynamics. DCX binds Fchitax-3 microtubules through its N-terminal DC domain, which accommodates the narrower inter-protofilament binding site in the 15-protofilament lattice. Remarkably, although Fchitax-3 induces the longitudinal lattice expansion characteristic of taxanes, DCX remodels its binding site towards its preferred compacted configuration. Thus, taxanes can modify microtubule structure in distinct ways while preserving lattice plasticity and the capacity to undergo conformational remodelling by microtubule-associated proteins. This contrasts with the comparatively rigid lattice of GMPCPP-stabilized microtubules. Consequently, interpretations of microtubule lattice states based on comparisons between taxane- and GMPCPP-stabilized microtubules may conflate structural differences with different degrees of lattice plasticity. Our findings establish the microtubule lattice as a malleable structural substrate whose drug-induced conformations can be further remodelled by cellular binding partners.
ER -