Artículo
Regulation of TIA-1 Condensates: Zn2+ and RGG Motifs Promote Nucleic Acid Driven LLPS and Inhibit Irreversible Aggregation
Autor/es | West, Danella L.
Loughlin, Fionna E. Rivero Rodríguez, Francisco Vankadari, Naveen Velázquez Cruz, Alejandro Corrales Guerrero, Laura Díaz Moreno, Irene Wilce, Jacqueline A. |
Departamento | Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-08-30 |
Publicado en |
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Resumen | Stress granules are non-membrane bound RNA-protein granules essential for survival during acute cellular stress. TIA-1 is a key protein in the formation of stress granules that undergoes liquid-liquid phase separation by ... Stress granules are non-membrane bound RNA-protein granules essential for survival during acute cellular stress. TIA-1 is a key protein in the formation of stress granules that undergoes liquid-liquid phase separation by association with specific RNAs and protein-protein interactions. However, the fundamental properties of the TIA-1 protein that enable phase-separation also render TIA-1 susceptible to the formation of irreversible fibrillar aggregates. Despite this, within physiological stress granules, TIA-1 is not present as fibrils, pointing to additional factors within the cell that prevent TIA-1 aggregation. Here we show that heterotypic interactions with stress granule co-factors Zn2+ and RGG-rich regions from FUS each act together with nucleic acid to induce the liquid-liquid phase separation of TIA-1. In contrast, these co-factors do not enhance nucleic acid induced fibril formation of TIA-1, but rather robustly inhibit the process. NMR titration experiments revealed specific interactions between Zn2+ and H94 and H96 in RRM2 of TIA-1. Strikingly, this interaction promotes multimerization of TIA-1 independently of the prion-like domain. Thus, through different molecular mechanisms, these stress granule co-factors promote TIA-1 liquid-liquid phase separation and suppress fibrillar aggregates, potentially contributing to the dynamic nature of stress granules and the cellular protection that they provide. |
Agencias financiadoras | National Health and Medical Research Council. Australia Australian Research Council Junta de Andalucía Ministerio de Ciencia e Innovación (MICIN). España |
Identificador del proyecto | APP1105801
DP200102737 BIO198 US-1254317 P18- FR-3487 P18-HO-4091 PGC 2018-096049- BI00 PID2021-126663NB-I00 |
Cita | West, D.L., Loughlin, F.E., Rivero Rodríguez, F., Vankadari, N., Velázquez Cruz, A., Corrales Guerrero, L.,...,Wilce, J.A. (2022). Regulation of TIA-1 Condensates: Zn2+ and RGG Motifs Promote Nucleic Acid Driven LLPS and Inhibit Irreversible Aggregation. Frontiers in Molecular Biosciences, 9, 960806. |
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Regulation of TIA-1 Condensates.pdf | 2.786Mb | [PDF] | Ver/ | |