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Sanders, David W.; Kedersha, Nancy; Lee, Daniel S.W.; Strom, Amy R.; Drake, Victoria; Riback, Joshua A.; Bracha, Dan; Eeftens, Jorine M.; Iwanicki, Allana; Wang, Alicia; Wei, Ming-Tzo; Whitney, Gena; Lyons, Shawn M.; Anderson, Paul; Jacobs, William M.; Ivanov, Pavel; Brangwynne, Clifford P.
Cell, 04/2020, Letnik: 181, Številka: 2Journal Article
Liquid-liquid phase separation (LLPS) mediates formation of membraneless condensates such as those associated with RNA processing, but the rules that dictate their assembly, substructure, and coexistence with other liquid-like compartments remain elusive. Here, we address the biophysical mechanism of this multiphase organization using quantitative reconstitution of cytoplasmic stress granules (SGs) with attached P-bodies in human cells. Protein-interaction networks can be viewed as interconnected complexes (nodes) of RNA-binding domains (RBDs), whose integrated RNA-binding capacity determines whether LLPS occurs upon RNA influx. Surprisingly, both RBD-RNA specificity and disordered segments of key proteins are non-essential, but modulate multiphase condensation. Instead, stoichiometry-dependent competition between protein networks for connecting nodes determines SG and P-body composition and miscibility, while competitive binding of unconnected proteins disengages networks and prevents LLPS. Inspired by patchy colloid theory, we propose a general framework by which competing networks give rise to compositionally specific and tunable condensates, while relative linkage between nodes underlies multiphase organization. Display omitted •Stress granule formation requires RNA-binding nodes with high network connectivity•Capping of nodes by ligands lacking connectivity prevents condensation•Protein disorder and RNA-binding specificity play non-essential, modulatory roles•Competition of RNP networks for connecting nodes controls multiphase organization With sufficient RNA-binding interfaces, diverse protein complexes can trigger stress-dependent multiphase condensates, whose composition and spatial organization is determined by overlapping interaction networks.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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