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Kane et al. show that cohesin is required for long-range, but not shorter-range, enhancer function at the Shh locus, implicating loop extrusion as a mechanism for keeping enhancer and target genes sufficiently close together for effective enhancer–promoter communication.
Episomal DNA silencing by Smc5/6 is a three-step process, with the first step involving Smc5/6 binding to and entrapment of the DNA, followed by recruitment of Smc5/6 to promyelocytic leukemia nuclear bodies by SLF2. The third step requires Nse2 but not its SUMO ligase activity.
The authors show that histone deacetylation maintains a high density of H3K9me3 methylated histones that transmit epigenetic memory for self-propagation of heterochromatin, which is critical for preventing untimely gene expression during development.
Sijacki et al. show how phosphorylation of FANCI by the ATR DNA damage kinase primes the FANCD2–FANCI clamp for ubiquitination. Phosphorylation promotes closure of the clamp, exposing a lysine for ubiquitination to initiate DNA cross-link repair.
The cryo-EM structure of CRL7FBXW8 shows that CUL7–RBX1 binds FBXW8–SKP1 in an F-box-independent manner. Bridged by FBXW8–SKP1, CRL7FBXW8 forms a multi-cullin E3 ligase complex with neddylated CUL1–RBX1, which ubiquitinates a substrate recruited to CUL7.
The cryo-EM structures reveal orphan receptor GPR119 as the receptor for LPC. The structures with biochemical and functional data highlight evidence for LPC function in glucose regulation, and provide templates for drug design targeting GPR119.
Foutel et. al. identify conformational buffering as a mechanism for functional selection in intrinsically disordered protein regions that allows robust encoding of a tethering function by a hypervariable disordered linker through compensatory changes in sequence length and composition.
The H-latch is a well-defined structural change occurring in PrPC bound to the neurotoxic antibody POM1, and its presence shows a positive correlation with neurotoxicity. Inhibition of the H-latch prolongs the lifespan of prion-diseased mice.
Elango et al. identify a new class of substrates on which the Fanconi anemia SLX4–XPF nuclease operates to mediate homologous recombination at DNA–protein replication fork barriers and promote cellular tolerance of DNA–protein cross-links.
An endogenous proteasome inhibitor was identified 30 years ago, but its mechanism remained unclear. Rawson et al. show that this inhibitor is present within the interior of the proteasome, where it simultaneously inhibits all six active sites.
Functional assays and cryo-EM structures show that ubiquitin binding and a cofactor drive protein quality-control client selection by the hybrid E2/E3 enzyme UBE2O.
Here, the authors find that histone demethylase Epe1-mediated stress resistance is regulated by proteasome-dependent truncation, allowing heterochromatin to reprogram gene expression that confers antifungal resistance to some fission yeast cells in the population.
Cryo-EM, X-ray crystallography and crosslinking mass spectrometry are harnessed to solve the structure of the full-length Rho-GEF P-Rex1, uncovering a two-layered mechanism of autoinhibition released upon Gβγ and PI(3,4,5)P3 binding.
This work reveals the structural and biochemical basis for phosphorylation-dependent day/night signaling by KaiC in the cyanobacterial circadian clock.
Clemons and colleagues identify a guided entry of tail-anchored proteins (GET) pathway in the pathogen Giardia intestinalis and characterize it structurally, revealing several previously unknown structures of the central protein Get3. The work resolves some important open questions and results in a comprehensive model for the insertion of tail-anchored membrane proteins.
Cryo-EM structures of human erythrocyte ankyrin-1 complex offer insights into the architecture of the RBC membrane and show how ankyrins can simultaneously recruit different membrane proteins to enable functional organization of membrane transport processes.
Single-molecule experiments reveal that condensin-induced DNA looping is stimulated by positive supercoils, and condensin preferentially binds near the tips of supercoiled plectonemes; upon loop extrusion, condensin collects nearby DNA plectonemes into a supercoiled loop.
Here authors visualize dynamics GAGA pioneer factor (GAF) association with chromatin in vivo in Drosophila hemocytes. The characterization of GAF kinetics provides a temporal mechanism for maintenance of open chromatin for transcriptional responses to homeostatic, environmental and developmental signals.
This comprehensive study of the most enigmatic serotonin receptor 5-HT5AR includes lots of pharmacological investigations, inactive and active state structures with antagonist, partial agonist and full agonists. Also, a highly potent and selective antagonist was developed.
Multiple cryo-EM structures of human glycogen synthase reveal the basis of inhibition by phosphorylation and allosteric activation by glucose-6-phosphate.