The T7 bacteriophage deactivates bacterial defence systems through T7K phosphorylation of nearly all host and phage proteins during infection.

Eriksson et al. conduct a global marine microbiome diversity analysis and demonstrate how the surface ocean latitudinal diversity gradient is disproportionately shaped by a few species-rich taxa. Mask...

A planetary-scale analysis of over 85,000 metagenomes establishes a framework for exploring the structure and drivers of global microbial habitats, revealing that generalist species bridge ecological ...

Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation. Yet, mechanistic knowledge of how endogenous ligands gate UPS decisions remains rudimentary. Here, we define control of UPS access to Tryptophan-2,3-dioxygenase (TDO2), which converts the essential amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert tryptophanemia. Using CRISPRi screening and biochemistry, we identify a CK2-FBXW11 kinase-E3 ligase cascade that generates and recognizes tandem TDO2 phosphodegrons when not protected by Trp. Trp binding to an exosite safeguards TDO2 from phosphorylation-dependent ubiquitylation. Effects of Trp analogs on CK2-FBXW11-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups are necessary for substrate shielding. Cryo-EM reveals how these moieties order a region proximal to the phosphodegrons; without Trp, this segment is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule allosterically stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade. ### Competing Interest Statement B.A.S. is a member of the scientific advisory boards of Proxygen and Lyterian. The other authors declare no competing interests. Max Planck Society, https://ror.org/01hhn8329 European Union, ERC AdvG, UPSmeetMet, 101098161 to BAS Boehringer Ingelheim Fonds, https://ror.org/00dkye506

Li et al. further develop a high-throughput peptide-centric local stability assay that speeds up sample preparation 100-fold and extends protein–ligand identification to membrane proteins, tissues and...

New tool combines biological knowledge with machine learning to help researchers extract meaningful insights from complex omics data.

Systematic mapping of protein-ligand interactions is essential for understanding biological processes and drug mechanisms. Peptide-centric local stability assay (PELSA) is a powerful tool for detectin...