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

Abstract

<jats:p>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 Ångstroms and may control the functional state of P-bodies and related phase-separated compartments.</jats:p>

Human coronaviruses disassemble processing bodies

“…There is increasing evidence in support of our hypothesis that the antiviral role of PB-localized enzymes is promoted by phase separation of molecules into PBs and that the antiviral function of these molecules is lost when PB granules decondense. This has been previously proposed for decapping complexes, the enzymatic activity of which is increased by phase separation and decreased in solution (3-5). However, for PB-localized enzymes that have established antiviral effects, (e.g.…”

“…That said, our evidence does not yet discern if the proposed antiviral role of PB-localized enzymes is promoted by phase separation of molecules into PBs or not; if so, we would predict that the antiviral function of these molecules is lost when PB granules decondense. Emerging evidence suggests that activity of the decapping enzymatic complex is increased by phase separation and decreased in solution [9,24,121]. Thus, we speculate that PBs are direct-acting antiviral granules that can restrict virus infection when present as visible condensates; for this reason, they are targeted for disassembly by most viruses.…”

“…PBs are ubiquitous, biomolecular condensates that form via liquid-liquid phase separation of proteins with regions of intrinsic disorder, and from RNA-protein and RNA-RNA interactions (1)(2)(3)(4)(5). PBs are comprised of the enzymes required for mRNA turnover, including those needed for decapping (Dcp2 and co-factors Dcp1a and Edc4/Hedls) and decay of the RNA body (5'-3' exonuclease Xrn1 and RNA helicase Rck/DDX6) and some components of the RNA-induced silencing complex (2,6).…”

“…decreased in solution(3)(4)(5). However, for PB-localized enzymes that have established antiviral effects, (e.g.…”

Phosphorylation of the NBDY Microprotein Promotes Dissociation of Biomolecular Condensates

“…cytoplasm [19][20] , recent evidence suggests that the activity of the mRNA decapping enzyme DCP2 is exquisitely controlled, both positively and negatively, by conformational changes and protein-protein interactions in the liquid droplet phase 21 .…”