Microtubule dynamics: an interplay of biochemistry and mechanics

Abstract

Microtubules are dynamic polymers of αβ-tubulin that are essential for intracellular organization, organelle trafficking and chromosome segregation. Microtubule growth and shrinkage occur via addition and loss of αβ-tubulin subunits, which are biochemical processes. Dynamic microtubules can also engage in mechanical processes, such as exerting forces by pushing or pulling against a load. Recent advances at the intersection of biochemistry and mechanics have revealed the existence of multiple conformations of αβ-tubulin subunits and their central role in dictating the mechanisms of microtubule dynamics and force generation. It has become apparent that microtubule-associated proteins (MAPs) selectively target specific tubulin conformations to regulate microtubule dynamics, and mechanical forces can also influence microtubule dynamics by altering the balance of tubulin conformations. Importantly, the conformational states of tubulin dimers are likely to be coupled throughout the lattice: the conformation of one dimer can influence the conformation of its nearest neighbours, and this effect can propagate over longer distances. This coupling provides a long-range mechanism by which MAPs and forces can modulate microtubule growth and shrinkage. These findings provide evidence that the interplay between biochemistry and mechanics is essential for the cellular functions of microtubules.

Microtubule Nucleation by Single Human γTuRC in a Partly Open Asymmetric Conformation

“…The apparent critical tubulin concentration required for γTuRC-mediated nucleation was 7.5 µM and hence significantly lower than the ~ 20 µM for spontaneous nucleation in solution in the absence of γTuRC (Fig. 3d, bottom right: microtubule elongation (grey arrow), γTuRC-mediated nucleation (purple arrow), spontaneous nucleation (green arrow) (Brouhard and Rice, 2018;Gard and Kirschner, 1987a;Roostalu and Surrey, 2017). However, γTuRC-mediated nucleation required a tubulin concentration still higher than the 2 µM tubulin threshold above which pre-existing microtubule plus ends elongate ( Fig.…”

Pseudo-repeats in doublecortin make distinct mechanistic contributions to microtubule regulation

“…The characterisation of distinct roles for each DC domain within DCX reflects the conformational diversity of tubulin as it transitions between unpolymerised and polymerised states (Brouhard and Rice, 2018), and is influenced by MT aging, damage and repair (Schaedel et al, 2015). In this context, different domains within MAPs effectively act as stage-specific tubulin chaperones specialising in interactions with different tubulin conformations.…”

3‐Arylindanones and related compounds as antiproliferative agents against colorectal cancer

“…Both compounds 7 and 22 showed antimitotic activity. Highly dynamic spindle microtubules are considered remarkable therapeutic targets for the development of cancer chemotherapeutics (Brouhard & Rice, ). Further, in molecular docking studies, there were fourteen residual amino acids in the binding pocket of compound 7 common to colchicine binding pocket.…”