Eukaryotic cells possess numerous dynamic membrane-less organelles, RNP granules, enriched in RNA and RNA binding proteins containing disordered regions. We demonstrate that the disordered regions of key RNP granule components, and the full-length granule protein hnRNPA1, can phase separate in vitro, producing dynamic liquid droplets. Phase separation is promoted by low salt concentrations or RNA. Over time, the droplets mature to more stable states, as assessed by slowed fluorescence recovery after photobleaching and resistance to salt. Maturation often coincides with formation of fibrous structures. Different disordered domains can co-assemble into phase-separated droplets. These biophysical properties demonstrate a plausible mechanism by which interactions between disordered regions, coupled with RNA binding, could contribute to RNP granule assembly in vivo through promoting phase separation. Progression from dynamic liquids to stable fibers may be regulated to produce cellular structures with diverse physiochemical properties and functions. Misregulation could contribute to diseases involving aberrant RNA granules.
Stress granules are assemblies of untranslating mRNPs that form from mRNAs stalled in translation initiation. Stress granules form through interactions between mRNA binding proteins that link together populations of mRNPs. Interactions promoting stress granule formation include conventional protein-protein interactions, as well as interactions involving intrinsically disordered regions of proteins. Assembly and disassembly of stress granules are modulated by a variety of post-translational modifications as well as a number of ATP dependent RNP or protein remodeling complexes, illustrating that stress granules represent an active liquid wherein energy input maintains their dynamic state. Stress granule formation modulates the stress response, viral infection, and signaling pathways. Persistent or aberrant stress granule formation contributes to neurodegenerative disease and some cancers.
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