Browse Articles

Many protein–protein interactions are mediated by compact amino acid stretches known as short linear motifs (SLiMs) that lack a stable tertiary structure. A study now uses high-throughput precision genome editing to decode the function of over 7,000 SLiMs across the human proteome, providing insights into their roles in cellular homeostasis.

Ambjørn and Meeusen et al. functionally characterize all reported and a comprehensive set of predicted short linear motifs (SLiMs) using base-editing screens, identifying 450 reported and 264 predicted SLiMs required for normal cell proliferation.

In this review, the authors discuss and contextualize the cellular responses launched after mitochondrial stress and note the importance of the emerging understanding in applying this new knowledge in relevant diseases.

Here, Li, Lu, Xia and colleagues identify the maternal complex MPU (PADI6–UHRF1–UBE2D), determine its cryo-electron microscopy structure and show that PADI6 maintains oocyte proteostasis by sequestering UBE2D with the assistance of UHRF1, thereby inhibiting protein ubiquitination. The study, thus, provides a molecular mechanism underlying PADI6-associated female infertility.

Kroczek et al show that degradation of DNAJC15 by OMA1 and AFG3L2 under stress limits mitochondrial protein import and OXPHOS biogenesis. Non-imported proteins lead to the induction of the unfolded protein responses from the endoplasmic reticulum.

The chromatin environment constitutes a mutable and tunable timer of early development that dictates timely and fine-tuned expression of certain transcriptional programs. In a recent study in Nature Structural & Molecular Biology, the authors describe a nuclear Z compartment that forms in early totipotent-like mouse cells.

Li, Li, Yang and Huang et al. show that ultraviolet-induced ribotoxic stress activates ZAK signaling to phosphorylate the Integrator subunit INTS12, thus promoting Integrator recruitment to CSB-bound, stalled RNA polymerase II (Pol II) and facilitating Pol II removal during efficient transcription-coupled nucleotide excision repair.

Leveraging long-read RNA sequencing and multiomics analyses, Cheon and Alvstad et al. systematically map transposable element (TE)-derived isoforms across species and cell states, revealing RNA quality control mechanisms regulating TE–gene chimeras that shape transcriptome plasticity.

METALoci, a new three-dimensional genome computational tool, reveals a major rewiring of regulatory interactions during sex determination. By combining this method with transgenic models, the authors identify a noncoding regulatory region at the Fgf9 locus and reveal that Meis genes are key regulators of sexual differentiation.

Google’s DeepMind presents AlphaGenome, the largest multimodal DNA sequence model for non-coding regions so far. It advances the state of the art in almost all prediction tasks and offers a new unified tool to study the effects of genomic variation on regulatory cellular mechanisms. However, opportunities for further improvement remain.

In this Review, Kotani and Nakatogawa discuss recent advances in our understanding of the molecular basis of autophagy induction and delineate how diverse mechanisms converge on core principles to ensure context-specific control of autophagy initiation.

Huang, Rigau and colleagues observe major changes in how DNA is organized in early germ cells before they start developing into sperm or eggs. These results show that germline removes structural ‘memory’ of DNA folding to start fresh for the next generation.

In this issue of Nature Structural & Molecular Biology, we are publishing two studies investigating the mechanisms of how bacteria fight phage invasion, and how phages fight back.

This study shows how the bacterial retron Eco2 defends against viruses. Phage nucleases trigger activation of Eco2, which cuts RNAs, shuts down protein production and stops phage replication.

Shajahan et al. unveil a repressive genomic compartment in totipotent-like cells, shaped by Zscan4 and guided by transient Z-DNA formation. This ‘Z compartment’ may be crucial for preserving totipotency in early embryos.

Pindi and Palermo review the contributions of deep learning structure prediction algorithms, physics-based simulations, neural networks, graph neural networks and generative models in engineering CRISPR systems and in understanding their mechanistic basis.

Tafur et al. determined the cryo-electron microscopy structure of the SEA complex (GATOR) bound to its substrate, the EGO complex (Ragulator–Rag), and showed that its GAP activity is essential for both rapid inactivation and reactivation of TORC1.