A disordered linker in the Polycomb protein Polyhomeotic tunes phase separation and oligomerization

TM Gemeinhardt and RM Regy and TM Phan and N Pal and J Sharma and O Senkovich and AJ Mendiola and HJ Ledterman and A Henrickson and D Lopes and U Kapoor and A Bihani and D Sihou and YC Kim and D Jeruzalmi and B Demeler and CA Kim and J Mittal and NJ Francis, MOLECULAR CELL, 85, 2128-2146 (2025).

DOI: 10.1016/j.molcel.2025.05.008

Biomolecular condensates are increasingly recognized as key regulators of chromatin organization, yet how their formation and properties arise from protein sequences remains incompletely understood. Cross-species comparisons can reveal both conserved functions and significant evolutionary differences. Here, we integrate in vitro reconstitution, molecular dynamics simulations, and cell-based assays to examine how Drosophila and human variants of Polyhomeotic (Ph)-a subunit of the PRC1 chromatin regulatory complex-drive condensate formation through their sterile alpha motif (SAM) oligomerization domains. We identify divergent interactions between SAM and the disordered linker connecting it to the rest of Ph. These interactions enhance oligomerization and modulate both the formation and properties of reconstituted condensates. Oligomerization influences condensate dynamics but minimally impacts condensate formation. Linker-SAM interactions also affect condensate formation in Drosophila and human cells and growth in Drosophila imaginal discs. Our findings show how evolutionary changes in disordered linkers can finetune condensate properties, providing insights into sequence-function relationships.

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