Biomolecular condensates amplify mRNA decapping by coupling protein interactions with conformational changes in Dcp1/Dcp2

Cells organize biochemical processes into biological condensates. P-bodies are cytoplasmic condensates enriched in factors important for mRNA degradation. P-bodies have been identified as sites of both mRNA storage and decay, but how these opposing outcomes may be achieved in condensates is unresolved. A critical step in mRNA degradation is removal of the 5-7-methylguanosine cap by Dcp1/Dcp2, which is highly enriched in P-bodies. Dcp1/Dcp2 activity is repressed in condensates in vitro and requires the activator Edc3. Activation of decapping is amplified in condensates relative to the surrounding solution due to stabilization of an autoinhibited state in Dcp1/Dcp2. Edc3 couples a conformational change in the Dcp1/Dcp2 active site with alteration of the protein-protein interactions driving phase separation to activate decapping in condensates. The composition-dependent regulation of enzyme activity in condensates occurs over length scales ranging from microns to [A]ngstroms and may control the functional state of P-bodies and related phase-separated compartments. HIGHLIGHTSO_LImRNA decapping in droplets is repressed C_LIO_LICatalytically inert droplets are activated by a change in condensate composition C_LIO_LIA switch in enzymatic activity requires a conformational change in condensates C_LIO_LICondensates amplify enzyme activation compared to surrounding solution C_LI