Microtubule (MT) nucleation is essential for organizing and regulating the cellular MT network. Nucleation from stabilized MT templates is a fundamental mechanism, yet its underlying process remains poorly understood. Here, we present a physics-based, structure-resolved mechano-chemical model that, unlike the prevailing critical nucleus framework, fully integrates MT dynamic instability into the nucleation process. In our model, growth, catastrophe, and shortening emerge from non-equilibrium conformational transitions of tubulin subunits and their interfaces. This framework quantitatively reproduces key experimental observations—including the high critical concentration, concentration-dependent delay time, and regulation by catastrophe-modulating proteins—within a unified mechanistic picture. The rate-limiting step is not forming a special nucleus but elongating a nascent MT beyond a detectable length without undergoing catastrophe. The observed delay arises from repeated cycles of growth, catastrophe, and regrowth, while persistent elongation at subcritical tubulin concentrations is enabled by memory of plus-end geometries inherited from earlier high-concentration growth.
Ma et al. (Sun,) studied this question.