Research articles

The authors use time-resolved cryo-electron microscopy to reveal the interactions of the redox-active cofactor TXNL1 with the human 26S proteasome and detect ATPase motor states that indicate burst-like mechanisms for hand-over-hand substrate translocation.

Teng and Zeng et al. use cryo-electron microscopy to show that the crescent scaffold of KICSTOR anchors GATOR1 to lysosomes and disruption of the interaction causes mTORC1 hyperactivation and TFE3 mislocalization. KICSTOR enables nutrient-dependent mTORC1 regulation by binding anionic lipids for lysosomal targeting.

Li et al. further develop a high-throughput peptide-centric local stability assay that speeds up sample preparation 100-fold and extends protein–ligand identification to membrane proteins, tissues and bacteria.

Malagobadan et al. show that a DICER1 hotspot mutation, previously thought to cause partial loss of function, also leads to unexpected gain of function by activating normally silent 3p passenger microRNAs, revealing a strand-switch mechanism in tumorigenesis.

The authors here show that the TRIM21–OTUD6A axis controls AKT activity through K27-linked ubiquitination, which is further regulated by S6K1-mediated phosphorylation, introducing a putative therapeutic strategy against AKT-driven cancers.

Jee et al. study a cancer hotspot allele of DICER1 that disrupts RNaseIIIb activity. Beyond ablating 5p hairpin cleavage, 3p passenger strands are globally upregulated and active. Thus, this setting induces both loss and gain of miRNA function.

Stowell et al. show that the intrinsically disordered region (IDR) of Puf3 binds the Ccr4–Not deadenylase complex using an extended interface. Phosphorylation of the IDR regulates the interaction to tune exonucleolytic activity in a graded manner.

Ye et al. define the structure and mechanisms of a bacterial pathway that performs ubiquitination-like protein conjugation, revealing new insights into the evolution and biological roles of ubiquitination pathways across kingdoms.

Yan et al. use cryo-EM to obtain structures that reveal how DNMT3A2 and DNMT3L cooperate to read histone signals and bind chromatin, illustrating a mechanism that controls DNA methylation and shapes epigenetic regulation.

Wang et al. combine structural and biochemical analyses to show how a bacterial defense system, Ec78 retron, employs reverse-transcriptase-derived DNA to regulate an ATPase–nuclease pair for phage defense.

Transient receptor potential channel subfamily M member 4 (TRPM4) is a cation channel that modulates various Ca²⁺-dependent physiological processes. Teixeira-Duarte et al. present human TRPM4 structures in various conformational states, providing insights into channel regulation by Ca²⁺, PtdIns(4,5)P₂ and adenosine triphosphate.

TRPM3 is an ion channel that helps the body sense heat and contributes to pain. The authors show that both heat and small chemical molecules switch it on through similar changes inside the protein.

The authors identify the human RNase MRP-specific proteins, RMP24 (C18orf21) and RMP64 (Nepro), define their role in 40S ribosome biogenesis, and reveal how disease-linked RMP64 mutations disrupt complex assembly.

Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.

The authors use selective ribosome profiling to define how and when factors for N-glycosylation and membrane insertion engage and disengage from the core Sec61 translocation channel during biogenesis of secretory and membrane proteins at the endoplasmic reticulum.

Goel et al. produce high-resolution three-dimensional genome structure mapping from mitosis to G1 phase to show unseen interactions between enhancers and promoters in prometaphase. Polymer modeling indicates the interactions are facilitated by chromosome compaction.

Li et al. show that a Lamassu defense system protects bacteria from phage infection by activating a lethal tetrameric DNA-cutting enzyme. In the absence of phages, a protein clamp holds the enzyme as an inactive monomer, preventing self-damage.

Using a new method called FoldTree, the authors compare proteins on the basis of their shape to construct more accurate family trees over long evolutionary timescales and capture distant relationships where sequence information becomes less reliable.

Fu et al. uncover the features that allow the HIV capsid to cross the permeability barrier of nuclear pores in an importin-independent manner, explaining how the viral genome can reach the nuclear compartment when infecting nondividing cells.

Here Schwämmle et al. develop CRISPR reporter screens to map transcription-factor-regulatory element interactions at the Xist locus, revealing a two-step mechanism integrating developmental and X-dosage signals to initiate X-chromosome inactivation.