Liquid-liquid phase separation (LLPS) of proteins has been an attractive field of study in recent years, as it has been shown to be involved in cellular processes such as transcription, stress responses, and metabolite production. Oligomerization has previously been shown in some individual protein systems to be essential for LLPS of those proteins. In this work, we propose that oligomerization may be a universal mechanism by which any protein system can enhance LLPS. We demonstrate that RNA-binding protein TDP-43 is capable of LLPS <i>in vitro</i> without the use of its C-terminal prion-like domain, in a manner dependent on the oligomerization of its N-terminal domain (NTD). We show that fusing TDP-43’s NTD to other proteins also enables or enhances their ability to LLPS, and we show that replacing TDP-43’s NTD with other oligomerization domains enhances LLPS proportionately to the state of oligomerization. Finally, we demonstrate that oligomerization is used by TDP-43 to LLPS <i>in vivo</i>, where removing oligomerization abrogates LLPS. We believe oligomerization is a general mechanism to enhance LLPS, and that it will likely be seen as an important part of phase-separating systems in the future.

Oligomerization as a general mechanism for enhancing liquid-liquid phase separation

ACS Spring Meeting 2021

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