Abstract 1705 Differential partitioning by disorder-mediated condensates

Selective compartmentalization of cellular contents is fundamental to the regulation of biochemistry. While membrane-bound organelles control composition by using a semi-permeable barrier, biomolecular condensates rely on interactions among constituents to determine composition. Condensates are formed by dynamic multivalent interactions, often involving intrinsically disordered regions (IDRs) of proteins, yet whether distinct compositions can arise from these dynamic interactions is not known. Here, by comparative analysis of proteins partitioned by two different IDR-mediated condensates, we find that distinct compositions arise through specific IDR-IDR interactions. Differentially partitioned proteins have their own IDRs that are necessary and sufficient for selective partitioning. These two sets of IDRs have distinct sequence features required for their partitioning. Swapping IDRs retargets proteins and their biochemical activity to different condensates. Our results demonstrate that IDR-mediated interactions create compositionally distinct condensates driven by the molecular grammars encoded within IDRs thereby enabling the spatial regulation of biochemistry within the cell. The authors thank the UTSW Proteomics Core for assistance with mass spectrometry experiments. This work was supported by a sponsored research agreement with Pfizer Centers for Therapeutic Innovation, Cancer Prevention Research Institute of Texas (CPRIT), National Institutes of Health (NIH), and The Welch Foundation Catalyst grant.