Nature Structural & Molecular Biology, Published online: 13 October 2026; doi:10.1038/s41594-026-01883-8Klose et al. provide structural insights into a supercomplex between the EMC and Spf1 that brings together cellular machines for membrane protein insertion and extraction into a single entity, providing a framework for integrated membrane protein quality control.

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MicroRNAs control gene expression by modulating the output and stability of messenger RNAs. How are these crucial regulators kept in check?

IMPRS-LM stands for International Max Planck Research School for Living Matter. We are interested in the molecular, chemical and physical properties

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

Most eukaryotic membrane proteins are inserted into the membrane at the endoplasmic reticulum (ER). This essential but error-prone process relies on molecular quality control machineries to prevent mi...

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Ubiquitin chains determine the fates of their modified proteins, including proteasomal degradation. Kiss et al. present UbiREAD, a technology to monitor cellular degradation and deubiquitination at hi...

PhD conference, interact 2025, organised in Munich, Germany. Great opportunity for PhD candidates to network with fellow early career researchers and learn about their future career opportunities.

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Many environmental toxins damage proteins, which then must be removed to avoid dangerous protein aggregation and disease. How cells dispose of chemically modified proteins has been unclear, but a discovery offers some clues. How the stress-response machinery eliminates damaged proteins.

SCF–FBXO31 scans proteins for C-terminal amidation and marks them for subsequent proteasomal degradation.

Kelch-domain KLHDCX E3 ligases bind substrate C-terminal glycines. This study reveals substrate selectivity by E3s with similar structures; C-degrons are perceived by a “C-terminus anchor motif”, whos...