Termination of Protofilament Elongation by Eribulin Induces Lattice Defects that Promote Microtubule Catastrophes

Curr Biol. 2016 Jul 11;26(13):1713-1721. doi: 10.1016/j.cub.2016.04.053. Epub 2016 Jun 16.


Microtubules are dynamic polymers built of tubulin dimers that attach in a head-to-tail fashion to form protofilaments, which further associate laterally to form a tube. Asynchronous elongation of individual protofilaments can potentially lead to an altered microtubule-end structure that promotes sudden depolymerization, termed catastrophe [1-4]. However, how the dynamics of individual protofilaments relates to overall growth persistence has remained unclear. Here, we used the microtubule targeting anti-cancer drug Eribulin [5-7] to explore the consequences of stalled protofilament elongation on microtubule growth. Using X-ray crystallography, we first revealed that Eribulin binds to a site on β-tubulin that is required for protofilament plus-end elongation. Based on the structural information, we engineered a fluorescent Eribulin molecule. We demonstrate that single Eribulin molecules specifically interact with microtubule plus ends and are sufficient to either trigger a catastrophe or induce slow and erratic microtubule growth in the presence of EB3. Interestingly, we found that Eribulin increases the frequency of EB3 comet "splitting," transient events where a slow and erratically progressing comet is followed by a faster comet. This observation possibly reflects the "healing" of a microtubule lattice. Because EB3 comet splitting was also observed in control microtubules in the absence of any drugs, we propose that Eribulin amplifies a natural pathway toward catastrophe by promoting the arrest of protofilament elongation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimitotic Agents / pharmacology*
  • Cattle
  • Crystallography, X-Ray
  • Furans / pharmacology*
  • Ketones / pharmacology*
  • Microtubules / drug effects
  • Microtubules / metabolism*
  • Tubulin / metabolism*


  • Antimitotic Agents
  • Furans
  • Ketones
  • Tubulin
  • eribulin