Is an Alternative Model for Microtubule Assembly Needed?

Abstract

The microtubule assembly and disassembly dynamic and mechanical properties are essential for many key cellular processes. Mathematical and computational modeling, especially coupled mechano-chemical modeling, has contributed greatly to the advancement of our understanding of microtubule dynamics. However, critical discrepancies exist between experimental observations and modeling results that need to be resolved before further progress towards a complete model can be made. The absence of such a model hinders progress both on our fundamental knowledge of microtubule dynamics, and on the design of new therapies based on detailed understanding of the process of microtubule assembly.Flat sheet structures ranging in size from several hundred nanometers to one micron long have often been observed at the growing ends of microtubules in in vitro studies. However, previous modeling studies predict these sheet structures to be rare intermediates of microtubule disassembly rather than important components of the assembly process. Studies on microtubule mechanical properties also produced observations not easily explained by the existing computational models.Cryo-electron microscopy based structural analysis shows that under certain in vitro conditions tubulins form tubes and ribbons where subunits interact laterally using two distinct interfaces, with only one type corresponding to that observed in microtubules. Although these structures are formed under non-physiological conditions (low temperature), similar interactions exist within the microtubule doublet of cilia and flagella. Also interestingly, the residues involved in the new type of interaction are highly conserved. We performed computational studies to compare the dynamics and mechanical properties of two alternative models, with and without the new type of lateral interactions. We checked them against existing experimental data through thorough analysis of the two models in the full parameter space. The results suggest that incorporation of the new type of lateral interactions can resolve existing controversies.