Eg5 Inhibitors have Contrasting Effects on Microtubule Stability and Spindle Integrity Depending on their Modes of Action

Abstract

Despite its fundamental importance to understanding the molecular bases of these cellular processes, a quantitative and testable mechanochemical model that describes how structural differences between kinesins alter kinetic steps in the ATPase cycle to produce functional changes in processivity is lacking. Here we use high resolution single-molecule microscopy to directly observe the stepping behavior of kinesin-1 and À2 motors with different neck linker lengths. We identify a one-head bound vulnerable state where a kinetic race between attachment of the tethered head and detachment of the bound head occurs, and find that its duration is negatively correlated with processivity. Using a cross-family comparative approach, we map functional differences back to structural differences to build an understanding of the design principles underlying motor processivity. Overall, our results provide a quantitative framework for understanding kinesin processivity both biophysically and as it pertains to the physiologically relevant emergent behaviors that result from its tuning.

Gli2 is required for the induction and migration of Xenopus laevis neural crest

“…Additionally, our last epistatic analysis showed that eg5 acts upstream of gli2. Since Eg5 is considered an essential kinesin during microtubule organization and stability (Chen et al, 2017) with a participation in NC development different from its classical function in cell division (Fernandez et al, 2014), it is conceivable that Eg5 could act in the process required for Gli2 translocation to the primary cilium of Xenopus NCC. Moreover, this kinesin is highly expressed in glioblastoma cells as it is the case of Gli2 (Taglieri et al, 2017).…”