STRUCTURAL PLASTICITY ALLOWS DOUBLECORTIN AND DRUG-STABILIZED MICROTUBULES TO ACCOMMODATE EACH OTHER

Microtubules, the dynamic components of cell structures, can undergo alterations in their architecture and interactions with cellular regulators due to small molecules, though the precise mechanisms remain not fully grasped. To investigate this phenomenon, researchers utilized the neuronal microtubule-associated protein doublecortin (DCX), known to preferentially recognize 13-protofilament microtubules, to examine lattices fortified by various taxanes, such as the fluorescent taxane Fchitax-3.

The findings indicate that DCX can bind to 15-protofilament Fchitax-3-stabilized microtubules, suggesting that DCX is not solely indicative of 13-protofilament architecture. Cryo-electron microscopy revealed that the fluorescent portion of Fchitax-3 integrates into inter-protofilament lateral contacts, elucidating its impact on microtubule architecture and dynamics.

DCX binds Fchitax-3 microtubules via its N-terminal DC domain, which accommodates the narrower inter-protofilament binding site found in the 15-protofilament lattice. Interestingly, despite Fchitax-3 causing longitudinal lattice expansion, similar to taxanes, DCX adjusts its binding site to its favored compacted structure. This adaptation allows taxanes to modify microtubule structure in unique ways while maintaining lattice pliability and the ability of microtubule-associated proteins to undergo conformational remodeling.

This observation contrasts with the more rigid lattice observed in GMPCPP-stabilized microtubules. Consequently, researchers must exercise caution when interpreting microtubule lattice states based on comparisons between taxane- and GMPCPP-stabilized microtubules, as structural differences may be mistakenly conflated with varying degrees of lattice plasticity.

The study underscores the microtubule lattice as a flexible structural substrate, with drug-induced conformations potentially further modulated by cellular binding partners.