Structural study of the effect of neurotoxic tubulin targeting agents on stabilized microtubules.

Microtubules (MTs) are dynamic nanomachines composed of tubulin and microtubule-associated proteins (MAPs). Despite their seemingly simple structure, MTs are regulated through multiple layers of complexity that modulate their dynamics and functions. MAPs interact with specific regions of MTs, influencing their behavior through distinct mechanisms.

In addition to physiological regulation by MAPs, small molecules that bind to tubulin or MTs introduce a non-physiological fourth level of modulation. These compounds can disrupt MT dynamics and are widely used in clinical applications, particularly as antitumor agents.

Understanding how MAPs recognize different structural regions of MTs is critical to deciphering MT regulation. Current hypotheses suggest that the chemical gradient created by nucleotide hydrolysis induces structural changes that are selectively recognized by MAPs. Notably, previous beamtime experiments indicate that these structural transitions can be chemically modulated at the taxane and laulimalide/peloruside binding sites.

However, regulation of MTs through the taxane site—the most common chemotherapeutic target for solid tumors—is associated with neurotoxicity. This toxicity likely arises from structural perturbations induced by taxane binding, which destabilize preformed axonal MTs.

To understand the mechanisms underlying this neurotoxic effect, we aim to:

Study the structural impact of neurotoxic tubulin-targeting agents on MTs under physiological conditions across different drug concentrations.
Measure the kinetic response of preassembled MTs to these drugs, correlating structural changes with their biological and biochemical effects.

We predict that these insights will clarify the molecular basis of neurotoxicity induced by tubulin-targeting chemotherapeutic agents and guide the development of safer therapeutic alternatives.