Articles

Fang and colleagues revealed cryo-electron microscopy structures of human THIK1, identifying two inner gates and a C-type selectivity filter gate, distinct from other two-pore-domain potassium channels. Their findings uncover the channel gating mechanism, offering insights for developing THIK1-targeted neurotherapeutics.

Here the authors show that the E3 ligase GID4 can be harnessed for targeted protein degradation and present the crystal structure of the GID4–PROTAC–BRD4 ternary complex to elucidate the underlying molecular mechanisms.

Here, Song and Li et al. show that autophagy-related 8 (Atg8) recruits Atg1 to the surface of autophagosomes to coordinate membrane expansion of the autophagy machinery. Artificial tethering of the Atg1 kinase domain to autophagosomal membranes boosts autophagy in multiple species.

Chai et al. use cryo-electron microscopy to systematically interrogate the conformational landscape of motor protein dynein. The reported structures reveal intermediate states in the mechanochemical cycle of dynein, the role of adenosine triphosphate and the communication mechanism with microtubules.

Padi and Godek et al. solve cryo-electron microscopy structures of protein phosphatase 2A (PP2A):B55 bound to p107 and Eya3, which, together with nuclear magnetic resonance dephosphorylation experiments, show how PP2A:B55 recruits specific substrates and how it achieves efficient dephosphorylation of phosphosites with high cellular fidelity.

Here, the authors identify SPIN1 as a member of the subcortical maternal complex (SCMC). The SCMC component FILIA protects H3K4me3 reprogramming and zygotic genome initiation by preventing nuclear entry of SPIN1.

Here Ishikawa et al. determine the cryo-electron microscopy structures of the PspCas13b–guide RNA complex alone and in complex with target RNA, as well as that of the dPspCas13b–ADAR2–guide RNA–target RNA complex, thereby providing mechanistic insights into RNA cleavage and editing.

Here, Arkinson et al. reconstitute NUB1-mediated FAT10 degradation by the human 26S proteasome and use biochemistry, cryo-EM and hydrogen–deuterium exchange to show that NUB1 acts as an ATP-independent chaperone to trap partially folded FAT10 for proteasome delivery.

Channelrhodopsins (ChRs) are primary tools for precise optical control over living cells. Structures of a viral ChR, OLPVR1, in closed (1.1 Å) and open (1.3 Å) states reveal the key details of its molecular mechanism.

Naydenova, Boyle and Pathe et al. report that Shigella uses the ubiquitin E3 ligase IpaH1.4 to evade lipopolysaccharide ubiquitylation in infected cells by degrading the host E3 ligase RNF213. Using cryo-electron microscopy, they present the structural basis of this interaction and the mechanism of immune evasion.

Mikulski et al. identify a distinct chromatin structure at clustered GBP innate immune genes that preserves a mitotically heritable memory of prior priming by interferon-γ.

Mai and colleagues present cryo-electron microscopy structures of the SPG11–SPG15 and AP5–SPG11–SPG15 complex, offering insights into mechanisms of autophagic lysosome reformation and retrograde trafficking.

Here the authors show that the disruption of OGT expression in mouse embryonic stem cells unleashes TET activity, causing genome-wide decreases in DNA methylation and increases in 5-hydroxymethylcytosine, leading to the derepression of transposable elements and, in certain cases, the activation of nearby genes.

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.

Lu et al. report a D compartment in Caenorhabditis elegans germ granules, formed by DEAD-box RNA helicase DDX-19 and nuclear pore proteins. This compartment anchors granules to nuclear pores, ensuring compartmentalization, RNA surveillance and germline immortality.

By using cryo-EM and biochemical assays, Loeff et al. reveal the mechanistic basis for the protective function of the oxidoreductase PYROXD1 that maintains the activity of the tRNA ligase complex under aerobic conditions.

Proper splicing requires efficient spliceosome assembly. Here the authors reveal that zinc finger protein 207 interacts with the U1 small nuclear ribonucleoprotein to accelerate spliceosome assembly by increasing the local concentration of splicing regulators through phase separation.

Qi et al. used cryo-electron microscopy to determine the structures of tau filaments from the brains of individuals with MAPT mutants V337M and R406W, known to give rise to frontotemporal dementias. They showed that the tau filaments adopted the Alzheimer fold.

Here, the authors show that ZBTB16, SALL4 and SOX3 regulate mouse stem cell renewal and sperm production through a three-dimensional interacting chromatin network that maintains undifferentiated spermatogonia and primes genes for spermatogonia development and meiosis.

Here the authors determine the high-resolution 3D chromatin architecture of mouse male germ cells during spermatogenesis and show that CTCF-mediated 3D chromatin dictates the gene expression program required for spermatogenesis.