Tibble Ryan W, Depaix Anaïs, Kowalska Joanna, Jemielity Jacek, Gross John D
Program in Chemistry and Chemical Biology, University of California, San Francisco, San Francisco, CA, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Nat Chem Biol. 2021 May;17(5):615-623. doi: 10.1038/s41589-021-00774-x. Epub 2021 Mar 25.
Cells organize biochemical processes into biological condensates. P-bodies are cytoplasmic condensates that are enriched in enzymes important for mRNA degradation and have been identified as sites of both storage and decay. How these opposing outcomes can be achieved in condensates remains unresolved. mRNA decapping immediately precedes degradation, and the Dcp1/Dcp2 decapping complex is enriched in P-bodies. Here, we show that Dcp1/Dcp2 activity is modulated in condensates and depends on the interactions promoting phase separation. We find that Dcp1/Dcp2 phase separation stabilizes an inactive conformation in Dcp2 to inhibit decapping. The activator Edc3 causes a conformational change in Dcp2 and rewires the protein-protein interactions to stimulate decapping in condensates. Disruption of the inactive conformation dysregulates decapping in condensates. Our results indicate that the regulation of enzymatic activity in condensates relies on a coupling across length scales ranging from microns to ångstroms. We propose that this regulatory mechanism may control the functional state of P-bodies and related phase-separated compartments.
细胞将生化过程组织成生物凝聚物。P小体是富含对mRNA降解重要的酶的细胞质凝聚物，已被确定为储存和降解的场所。这些相反的结果如何在凝聚物中实现仍未得到解决。mRNA去帽紧接在降解之前，并且Dcp1/Dcp2去帽复合体在P小体中富集。在这里，我们表明Dcp1/Dcp2活性在凝聚物中受到调节，并且取决于促进相分离的相互作用。我们发现Dcp1/Dcp2相分离使Dcp2中的非活性构象稳定，从而抑制去帽。激活剂Edc3引起Dcp2的构象变化，并重新连接蛋白质-蛋白质相互作用以刺激凝聚物中的去帽。非活性构象的破坏会使凝聚物中的去帽失调。我们的结果表明，凝聚物中酶活性的调节依赖于从微米到埃的跨长度尺度的耦合。我们提出这种调节机制可能控制P小体和相关相分离区室的功能状态。
