In the latest issue of Science the Forman-Kay lab demonstrate that as proteins transition from the bulk solution to a phase separated condensate in a test tube, this regulates their ability to affect translation and deadenylation in the same manner observed in the cell. Partitioning of components of the translational machinery away from the mRNA can block translation while the unique condensate environment can activate deadenylation.
A previous dogma in biochemistry posited that a protein’s function depends on its fixed three-dimensional structure. However, experimental and bioinformatics analyses suggest that about 35% of the human proteome does not fold into stable structures, and is instead intrinsically disordered. It is now understood that many of these intrinsically disordered protein regions can contribute to the formation of membrane-less organelles through a process known as phase separation. Similar to the separation of oil and water, specific proteins and nucleic acids can assemble to form cellular membrane-less compartments (referred to as biomolecular condensates) that are distinct from classical membrane-bound organelles. Evidence for the cellular function of phase separation has been more limited than observation of condensates, with some wondering if phase separation is merely a by-product of the concentrated cellular milieu. Also, there is confusion about how intrinsically disordered protein regions can interact within condensed membrane-less compartments to facilitate biochemical processes.
The Forman-Kay lab tackled these questions by recapitulating a model condensate with the intrinsically disordered protein regions from two RNA-binding proteins, FMRP and CAPRIN1 and RNA (TH Kim*, B Tsang*, RM Vernon, N Sonenberg, LE Kay, JD Forman-Kay, Science 365, 825–829, 2019). Both proteins are involved in mRNA stability and translational regulation and contain mutations linked to neurodevelopmental disorders. Using nuclear magnetic resonance spectroscopy, they characterized interactions between specific residues within the condensates. In this model condensate system, they demonstrate that different condensate compositions and phosphorylation patterns can regulate translation and deadenylation in the same manner observed in the cell. Partitioning of components of the translational machinery away from the mRNA can block translation while the unique condensate environment can activate deadenylation. These results provide biophysical insights into the interactions underlying phase separation and the biological processes occurring within them.
