Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization.

TitleCompeting Protein-RNA Interaction Networks Control Multiphase Intracellular Organization.
Publication TypeJournal Article
Year of Publication2020
AuthorsSanders, DW, Kedersha, N, Lee, DSW, Strom, AR, Drake, V, Riback, JA, Bracha, D, Eeftens, JM, Iwanicki, A, Wang, A, Wei, M-T, Whitney, G, Lyons, SM, Anderson, P, Jacobs, WM, Ivanov, P, Brangwynne, CP
Date Published2020 04 16
KeywordsBiophysical Phenomena, Cell Line, Tumor, Cytoplasm, Cytoplasmic Granules, Cytoplasmic Structures, Humans, Intrinsically Disordered Proteins, Liquid-Liquid Extraction, Organelles, Protein Interaction Maps, RNA, RNA Recognition Motif Proteins

<p>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.</p>

Alternate JournalCell
PubMed ID32302570
PubMed Central IDPMC7816278
Grant ListR00 GM124458 / GM / NIGMS NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R35 GM126901 / GM / NIGMS NIH HHS / United States
F32 GM130072 / GM / NIGMS NIH HHS / United States
U01 DA040601 / DA / NIDA NIH HHS / United States
K99 GM124458 / GM / NIGMS NIH HHS / United States
R01 GM126150 / GM / NIGMS NIH HHS / United States