Type I and type II inhibitors differentially affect LRRK2 filament formation around microtubules, revealing an important consideration for Parkinson’s disease drug development.

A new chemistry-based super-resolution imaging framework is described, enabling 3D, laser-free, highly sensitive and ultralong-term imaging of live cells which overcomes the limitations in spatiotempo...

A Kaggle challenge for particle picking in experimental cryo-electron tomography data delivered new machine learning algorithms that outperformed state-of-the-art software and provides a critical refe...

Many computational problems possess the following three features: (1) the problem could be solved efficiently if a linear operator could be diagonalized, (2) direct diagonalization is infeasible due t...

Focused ion beam (FIB)-milling has been adapted to thin frozen cells for visualization of macromolecular structures in situ with cryogenic electron microscopy. However, only a few large and abundant c...

Resource for Biocomputing, Visualization amd Informatics (RBVI), and its precursor, the Computer Graphics Laboratory (CGL), develops cutting-edge interactive software tools and advanced web-based comp...

Mitochondrial function depends on the maintenance of its genome, and disruptions in copy number and distribution are hallmarks of mitochondrial disorders. Mitochondrial DNA (mtDNA) replication is spat...

Early enthusiasm for the “cellular revolution” in cryo-electron tomography (cryo-ET) was largely driven by the promise of resolving protein structures…

AreTomoLive is an accelerated preprocessing pipeline for cryo-electron tomography that streamlines tomographic alignment, reconstruction and contrast enhancement. This pipeline prioritizes automation ...

Downes et al. use in situ cryo-electron tomography and super-resolution fluorescence microscopy to define ER exit site architecture in unperturbed human cells. They visualize ribosome-exclusion zones ...

AP3 generates clathrin-free carriers on endosomes by organizing via ARF1 dimers into elongated membrane-deforming arrays.

In situ cryo-ET reveals how gap junction channels organize into plaques via the interactions between intracellular domains.

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

Resident proteins of the Golgi recycle in vesicles and the protein GOLPH3 enables the COPI vesicle coat to accomplish this.