Heterotypic interactions in the dilute phase can drive co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex

Abstract

Prion-like domains (PLDs) are low-complexity protein sequences enriched within nucleic acid-binding proteins including those involved in transcription and RNA processing. PLDs of FUS and EWSR1 play key roles in recruiting chromatin remodeler mammalian SWI/SNF complex to oncogenic FET fusion protein condensates. Here, we show that disordered low-complexity domains of multiple SWI/SNF subunits are prion-like with a strong propensity to undergo intracellular phase separation. These PLDs engage in sequence-specific heterotypic interactions with the PLD of FUS in the dilute phase at sub-saturation conditions, leading to the formation of PLD co-condensates. In the dense phase, homotypic and heterotypic PLD interactions are highly cooperative, resulting in the co-mixing of individual PLD phases and forming spatially homogeneous ternary co-condensates. Heterotypic PLD-mediated positive cooperativity in protein-protein interaction networks is likely to play key roles in the assembly of SWI/SNF complexes and their co-phase separation with transcription factors containing homologous low-complexity domains.

SWI/SNF chromatin remodelers in prostate cancer progression

“…The incorporation of ARID1A/B, ARID2, or GLTSCR1/1L on to the core seeds the assembly of additional subunits to form cBAF, PBAF, or GBAF (Figure 2). Subunits unique to a particular complex are involved in modulating enzymatic remodeling activity, recognizing DNA/histone substrates, recruiting additional transcriptional regulators or promoting heterotypic phase separation (Kuang et al, 2021;Davis et al, 2023;Patil et al, 2023). The HUGO Gene names and the many aliases of SWI/SNF subunits are listed in Table 2.…”