News & Views

Accurately interpreting density maps into atomic models is a central yet challenging goal of cryo-EM. Two studies now reveal distinct ways in which protein structure prediction can be incorporated into cryo-EM model building to enable more accurate and robust automated construction of protein atomic models from density maps.

For Okazaki fragments to efficiently mature, RNA primers need to be removed. A recent study in Nature Structural & Molecular Biology implicates ADAR1 in editing mismatched primers to promote unabated lagging-strand synthesis, via oxidation-dependent dimerization and activation of ADAR1.

The mechanisms that confine replication-dependent histone expression to S phase of the cell cycle remain unclear. Studies in Drosophila and cultured human cells show that non-nucleosomal histone H4 acts in a negative feedback loop to curtail histone gene expression at the end of S phase.

Artificial intelligence (AI) is advancing genome editing, from predictive modeling to generative design. Emerging generative AI tools such as RFdiffusion, AlphaFold 3 and ESM now facilitate the de novo design of linkers, inhibitors and enzymes. We highlight work where AI-driven design is used to enhance the precision of mitochondrial cytosine base editors.

To start, or not to start, that is the recurring question faced by eukaryotic ribosomes as they scan mRNA for translation start sites. A study now shows that two opposing initiation factors, which bind the ribosome in a mutually exclusive manner, assist in this decision-making process.

Protein sequence signatures suggest that eons ago, a bacterial glutamate transporter lost its sodium coupling to make way for a shift to proton coupling. A study now maps this ancient transition in biochemical and structural detail to better understand how secondary transporters control their energetics.

A study reveals how the TRAPPIII complex and Atg2 establish membrane contact sites between the growing autophagosomal membrane and the endoplasmic reticulum, coordinating Rab GTPase signaling and lipid transfer to drive autophagosome formation.

A recent high-resolution structure of USP30 bound to a selective inhibitor identifies a cryptic binding pocket formed through a conformational switch in the catalytic domain of the enzyme. This mechanistic insight opens a door to structure-guided design of mitophagy-enhancing compounds.

Sudden loss of lysosomal acidity triggers a rapid response. Two studies now identify the metazoan RAVE (mRAVE) complex as essential for V-ATPase reassembly and activation under such conditions; map interactions between mRAVE and V-ATPase; and identify a link to CASM, a non-canonical autophagy pathway.

Efficient mitophagy is essential for neuronal health. A study now shows that loss of VPS13D in neurons impairs mitochondrial clearance, gasdermin E activation, mitochondrial DNA release and microglial STING signaling. This neuroimmune mechanism promotes microglial responses that lead to neuronal dysfunction and loss.

How metabolic fitness in cancer clones is established and selected during dissemination and colonization remains enigmatic. A study in Nature now shows that disseminated pancreatic cancer cells bifurcate to seed the lung or liver on the basis of PCSK9 levels and the availability of microenvironmental cholesterol.

Maturation of snRNAs, key parts of the spliceosome, involves nuclear export of newly synthesized snRNAs to the cytoplasm. PHAX is known to mediate snRNA export in a phosphorylation-dependent manner, but the underlying mechanism remains elusive. A cryo-EM structure of a PHAX-containing snRNA export complex now provides insights into the pathway.

Radial spokes link the doublet microtubules at the periphery of the cilium to the central pair complex at its core. The detailed morphology and function of the radial spoke 3 (RS3) complex was unknown, but a new study reports its structure and reveals its role in metabolism.

Constitutive heterochromatin can promote piRNA transcription, a crucial step in genome defense. Two studies now show that piRNA transcription in Drosophila is regulated by the dual histone marks H3K27me3 and H3K9me3, and piRNA transcription in Caenorhabditis elegans is enhanced by H3K27me3, gene clustering and phase separation.

Germ granules contribute to the intergenerational transmission of small RNA-mediated silencing in germ cells. A study in Caenorhabditis elegans now investigates the function of the RNA helicase DDX-19 at the interface between the nuclear pore and the cytoplasmic germ granules.

Cell migration is a prerequisite for cancer cell invasion and metastasis. The highlighted study shows that UFMylation of ARPC4 facilitates ARP2/3 complex-mediated lamellipodia formation, thereby promoting cancer cell migration, invasion and metastasis.

Centrosomal protein assemblies can lead to mitotic spindle dysfunction and abnormal cell division. Two studies published in this issue unveil the molecular choreography orchestrated by TRIM37 in blocking the accumulation of these structures in a remarkable fashion that resembles viral capsid recognition.

Two papers offer a first glimpse at complexes of the helicase-like domain of DNA polymerase θ (Polθ-HD) bound to DNA. Together, they provide structural insights into how the dimeric form of Polθ-HD grabs and aligns single-stranded DNA tails near the 3′ termini, a process that is accompanied by large conformational changes within Polθ-HD.