Structure-Based Mechano-Chemical Modeling of Microtubule Nucleation

Microtubule (MT) nucleation is essential for organizing and regulating the cellular MT network. Nucleation begins from two types of templates: 1) Seed MTs – tubelike templates resembling normal MTs, and 2) γ-tubulin ring complexes (γTuRCs) – dynamic templates that must undergo closure to become tubelike. While nucleation from seed MTs is the foundation of the process, nucleation from γTuRCs involves additional complexity. The underlying mechanisms in both cases have remained elusive. Here, we present a structure-based mechano-chemical model that integrates MT dynamic instability with stepwise γTuRC closure, offering a comprehensive view of MT nucleation. Contrary to the prevailing “critical nucleus” framework, we found that nascent MTs do not need to form a specific structure to initiate growth. However, catastrophes (stochastic switches from growth to shortening) reduce the chance that nucleation can be detected. In contrast to the commonly held view of γTuRC as a simple activation switch, γTuRC actually functions as an active extension of the MT lattice, directing the construction of the nascent MT. Conformational changes in γTuRC subunits during closure are analogous to the structural transitions of tubulins within the MT. These changes maintain a sheetlike structure during the nascent MT formation, which resists catastrophes and thereby promotes successful nucleation. This unified framework resolves many longstanding experimental puzzles and opens new paths for understanding cellular functions, enabling new strategies for drug developments.

Author dc:creator

• Kenneth K. Tsui (23291326)

• Biology, Bioinformatics
• Biophysics, General
• Biology, Cell
• Biology, Molecular
• Engineering, Biomedical

Statement dc:rights

• In Copyright

DOI dc:identifier

https://doi.org/10.25417/uic.31451074.v1

OAI identifier oai:identifier

oai:figshare.com:article/31451074