Competing protein-RNA interaction networks control multiphase intracellular organization

By David W. Sanders, N. Kedersha, Daniel S. W. Lee, Amy R. Strom, Victoria Drake, Joshua A. Riback, Dan Bracha, J. Eeftens, Allana G Iwanicki, Alicia Wang and 7 more. Cell, 2020

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Summary: Liquid-liquid phase separation (LLPS) mediates formation of membraneless condensates, such as those associated with RNA processing, but the rules that dictate their assembly, sub-structure, 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/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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/aea900b5cf52a229dc8b4fc6f39d838a680e1456