IDR acquisition from human ortholog reprograms Snf11 to form HDAC-compartmentalizing condensates and drives yeast flocculation

Liquid-liquid phase separation (LLPS) regulates protein function by organizing proteins into dynamic condensates, yet how divergence in LLPS among orthologs gives rise to species-specific functional outputs remains poorly understood. Here, we show that intrinsically disordered regions (IDRs) act as transferable modules whose sequence composition encodes phase separation capacity and functional outputs. Incorporating the QPGY domain from human SS18 into its yeast ortholog Snf11 yields a chimeric protein (Snf11-QPGY) that forms dynamic intracellular condensates. These condensates activate the adhesion genes FLO1 and FLO11 , triggering calcium-dependent flocculation absent in wild-type cells. Mechanistically, Snf11-QPGY sequesters histone deacetylase subunit Rpd3 within condensates, reducing its occupancy at FLO promoters and promoting histone acetylation and transcriptional activation. Substituting QPGY with a heterologous LLPS-competent IDR restores condensate formation but does not recapitulate QPGY-driven transcriptional-phenotypic outputs. These findings reveal how evolutionary diversification of IDR sequences drives functional divergence among orthologs and offer a framework for engineering IDR-dependent regulatory modules.