Droplet growth, Ostwald's rule, and emergence of order in Fused in Sarcoma

• 成果类型: Article
• 署名作者: Maksudov, Farkhad; Mugnai, Mauro L.; Dominguez, Laura; Makarov, Dmitrii E.; Thirumalai, D.
• 署名单位: University of Texas System; University of Texas Austin; Georgetown University; Universidad Nacional Autonoma de Mexico; University of Texas System; University of Texas Austin
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2519135123
• 发表日期: 2026-01-27
• 页码: e2519135123
• 关键词: intrinsically disordered proteins; Ostwald's rule; Phase separation; low-complexity sequences; rates offibril formation; BIOMOLECULAR PHASE-SEPARATION; liquid droplets; protein; physics; transitions; granules; kinetics; fibrils; monomer; domain

摘要

The low-complexity domain of Fused in Sarcoma (FUS-LC) undergoes phase separation, forming a dense, liquid-like phase that gradually matures into an ordered, gel-like state over long-time scales. During the maturation process, specific regions of the FUS-LC sequence-core-1, core-2, and core-3-become structured, giving rise to non-polymorphic fibrils. Coarse-grained simulations predict that kinetically the least stable fibril-like core-3 forms first while the most stable core-1 appears last, in accord with Ostwald's rule of stages. The fibril structure of the C-terminal core-3, predicted using AlphaFold, shows that a beta-strand appears in this region early during droplet formation and triggers FUS-LC assembly. Multichain simulations, which ensure the equality of the chemical potentials between the phases, show that the dense phase forms through nucleation and coarsening, resembling Ostwald ripening. The approaches developed here are broadly applicable and could help uncover assembly mechanisms in other intrinsically disordered proteins like TDP-43, which shares key features with FUS-LC.