Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains

Anne Bremer, Mina Farag, Wade M. Borcherds, Ivan Peran, Erik W. Martin, Rohit V. Pappu, Tanja Mittag

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Prion-like low-complexity domains (PLCDs) have distinctive sequence grammars that determine their driving forces for phase separation. Here we uncover the physicochemical underpinnings of how evolutionarily conserved compositional biases influence the phase behaviour of PLCDs. We interpret our results in the context of the stickers-and-spacers model for the phase separation of associative polymers. We find that tyrosine is a stronger sticker than phenylalanine, whereas arginine is a context-dependent auxiliary sticker. In contrast, lysine weakens sticker–sticker interactions. Increasing the net charge per residue destabilizes phase separation while also weakening the strong coupling between single-chain contraction in dilute phases and multichain interactions that give rise to phase separation. Finally, glycine and serine residues act as non-equivalent spacers, and thus make the glycine versus serine contents an important determinant of the driving forces for phase separation. The totality of our results leads to a set of rules that enable comparative estimates of composition-specific driving forces for PLCD phase separation. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)196-207
Number of pages12
JournalNature Chemistry
Volume14
Issue number2
DOIs
StatePublished - Feb 2022

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