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Identifying the compositional features facilitating recruitment of prion‐like domains to stress granules

Stress granules are highly dynamic nonmembranous cytoplasmic RNA‐protein assemblies that form via interactions between mRNAs stalled in translation initiation and RNA‐binding proteins. Many of the RNA‐binding proteins in stress granules contain prion‐like domains (PrLDs). PrLDs are intrinsically disordered protein domains that compositionally resemble yeast prion domains; some PrLDs have been identified as playing a key role in stress granule formation. PrLDs are thought to be recruited to stress granules in part by liquid‐liquid phase separation (LLPS). Mutations in various RNA binding proteins containing PrLDs are associated with degenerative diseases, including Amyotrophic Lateral Sclerosis. These mutations are associated with the formation of cytoplasmic inclusions that share common components with stress granules, suggesting that the mutations perturb stress granule dynamics. However, the sequence features that drive recruitment of PrLDs into stress granules have yet to be completely defined. We recently demonstrated that many PrLDs are sufficient for stress granule recruitment in yeast, and that this recruitment is driven largely by amino acid composition. Here, we utilize synthetic prion‐like domains to rigorously examine the compositional features driving stress granule recruitment. We show that based solely on amino acid composition, we can rationally design synthetic PrLDs that are recruited to stress‐induced assemblies. Surprisingly, although aromatic amino acids are widely believed to play a key role in recruitment of PrLDs to stress granules, we find that aliphatic amino acids can functionally replace aromatic amino acids in supporting recruitment.