Volume 30 Issue 6, June 2023

Volume-regulated anion channels (VRACs) are critical for cell volume regulation, neuron–glia interaction, metabolism, and immunity. They are formed as heteromers of LRRC8 proteins with unknown stoichiometry. Two papers now reveal the structures of heteromeric LRRC8A and LRRC8C channels, providing insights into channel assembly and gating.

Gabapentinoids are first-line treatments for chronic pain but are associated with adverse side effects. A cryo-EM structure of gabapentin bound to its interaction site on the calcium channel α₂δ subunit now paves the way for the rational design of analgesics with greater selectivity and a reduced potential for adverse effects.

The correction of errors during mitochondrial DNA replication by the proofreading function of DNA polymerase-γ is crucial for maintaining the integrity of the mitochondrial genome and the production of cellular energy. Using cryo-electron microscopy, several steps of the DNA polymerase-γ proofreading pathway have been revealed at near-atomic resolution.

Here, the authors describe the composition, architecture, functions and mechanisms of the SMC (structural maintenance of chromosomes) complex Smc5/6 in chromosomal replication and repair, as well as its involvement in disease.

Gabapentinoid drugs are widely used for pain, epilepsy and mental disorders. Chen et al. report the structure of a gabapentin-bound brain and heart calcium channel, revealing the gabapentin binding site and isoform-selective binding determinants.

A systematic survey of the budding yeast proteome identifies hundreds of post-transcriptional regulators. Regulatory activity is enriched in RNA-binding proteins but lies outside the RNA-binding domains, often within intrinsically disordered regions.

Here, Zhouyan et al. present the structure of yeast SIN3–HDAC complex Rpd3L, revealing a distinctive organization mechanism compared with other class I HDAC complexes. The authors observe that two distinct arms hang on a T-shaped scaffold formed by two coiled-coil domains.

Günsel et al. unravel the structural and functional properties of OEP21, a major metabolite channel in the chloroplast outer envelope, and show that this porin utilizes a promiscuous mechanism to control the passage of a distinct set of substrates.

Here, the authors reveal the architecture of the TRAP complex bound to the translating ribosome and Sec61 translocon, explaining its function in insertion and secretion of proteins, including the insulin hormone, at the endoplasmic reticulum membrane.

Here the authors use cryogenic electron microscopy to solve the Arabidopsis thaliana Argonaute10–guide RNA complex with and without a target RNA representing a slicing substrate, to provide insights into the slicing mechanism of a eukaryotic Argonaute.

Here the authors show that PIAS3/SENP1-mediated poly-SUMOylation of MAVS regulates its interaction with IRF3, whose SUMO-interacting motif (SIM) guides binding to SUMOylated MAVS. IRF3 phosphorylation, close to its SIM, dismantles SUMO-dependent aggregates and releases activated IRF3.

Here, using proteomics, molecular biology and sequencing, the authors demonstrate that OGT-dependent O-GlcNAcylation of H4S47 is important for replication-origin activation, presumably through regulating DDK-induced phosphorylation of the MCM complex.

Using cryo-EM, the authors here show that Polγ transitions from replication to error correction by unwinding the DNA, rotating, and backtracking to move the mismatch to the exonuclease site for proofreading.

The authors perform cryo-EM of pre-tRNA in complex with the human tRNA splicing endonuclease complex TSEN to understand the basis of pre-tRNA recognition and processing by TSEN.

The authors provide cryo-EM reconstructions of human transfer RNA splicing endonuclease during substrate recognition, rationalizing disease-relevant mutations.

Using cryo-EM structures, single-molecule fluorescence and electrophysiological studies, Kern et al. show how LRRC8A:C volume-regulated channels assemble into heteromers and use pore-bound lipids to block conduction in a closed state.

Here, the authors determine the structural basis of how SGO1 protects centromeric cohesin from WAPL-mediated release until the kinetochores and the microtubules have formed functional attachments. In addition, they show that SGO1 and CTCF bind cohesin in a similar manner, suggesting a potential universal mechanism of cohesin control.