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Acyl-CoA oxidases, which play important roles in primary and secondary metabolism, are not known to be regulated by ATP. Here, the authors uncover the mechanism whereby ATP binds to an acyl-CoA oxidase, enhancing its affinity for its FAD cofactor and stimulating its enzymatic activity.

The ESCRT pathway is crucial for membrane remodelling in eukaryotes. Here, Hatano et al. explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system in Asgard archaea, the closest living relatives of eukaryotes.

DNAJC12 variants cause parkinsonism. Here, the authors show that DNAJC12 stabilizes tyrosine hydroxylase, a crucial enzyme in dopamine synthesis, and identify key structural motifs for this interaction, explaining the pathogenesis of truncated variants.

End-of-life nonhuman primates can be used to screen pools of lipid nanoparticles for clinical safety studies.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Lymphocyte activation gene-3 (LAG3) is an immune checkpoint protein recently approved as a target for anti-melanoma therapy. Here, the authors solve the structure of mouse LAG3 bound to MHC-II to show that LAG3 blocks MHC-II/CD4 interactions, thereby implicating a potential mechanism of LAG3-mediated immune suppression.

In a post-hoc analysis of circulating tumor DNA (ctDNA) features from patients with metastatic prostate cancer treated with [¹⁷⁷Lu]Lu–PSMA-617 or cabazitaxel in the randomized phase 2 TheraP trial, low ctDNA levels at baseline were predictive of clinical benefit from [¹⁷⁷Lu]Lu–PSMA-617, and PTEN or ATM alterations were identified as potential biomarkers of response.

Stabilized, native-like trimers of the HIV envelope protein, such as SOSIP trimers, are potential antigens for an HIV vaccine. Here, the authors generate a SOSIP trimer based on the consensus sequence of group M isolates, determine its structure and exposure of common epitopes, and show immunogenicity in rabbits and non-human primates.

Remote tumours cause liver dysfunction by releasing extracellular vesicles and particles containing palmitic acid, which induces TNF signalling in Kupffer cells, resulting in inflammation, fatty deposits and metabolic dysregulation, thus both reducing the efficacy and increasing the toxicity of chemotherapies.

A cryo-electron microscopy structure of the yeast pheromone receptor Ste2, a class D G-protein-coupled receptor, in its active state reveals that Ste2 is a homodimer that couples to two G proteins.

The transmembrane export apparatus regulates protein secretion through bacterial type III secretion systems. New structural data indicate that MxiA, a major component of the apparatus, assembles in a nonameric ring. This and additional structural information provide a framework for understanding how protein secretion is controlled.

Formation of the mitotic checkpoint complex (MCC) is catalysed by a phosphorylation-dependent scaffold. This work provides structural details of how a tripartite Mad1:Bub1:Cdc20 complex presents Cdc20 to Mad2, triggering open-to-closed conversion of Mad2 to assemble the MCC.

Partitioning of FtsN and the septal peptidoglycan synthesis complex between an active synthesis track and an inactive denuded glycan track coordinates opposing peptidoglycan synthesis and degradation activities in E. coli.

Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.

A lipid nanoparticle is used to deliver mRNA to hematopoietic stem cells in macaques.

Nanoparticles are a promising approach to increase immunogenicity of protein antigens for vaccines. Here, Brouwer et al. design self-assembling, two-component protein NPs that present native-like SOSIP trimers of HIV envelope protein and determine immunogenicity in a small animal model.

TssA is an important component of the bacterial type VI secretion system (T6SS). Here, Dix et al. integrate structural, phylogenetic and functional analysis of the TssA subunits, providing new insights into their role in T6SS assembly and function.

The mechanism behind Trim-Away, a protein-depletion approach using E3 ligase, TRIM21 and an antibody against the target, is now clarified, allowing expansion of the toolbox.

This study reports unexpected structural diversity in computationally designed protein assemblies due to subunit flexibility. Fixing flexibility in one design restores the intended architecture, suggesting a strategy to design dynamic assemblies.

On exposure to low-frequency ultrasound, porphyrin microbubbles form nanoparticles that possess the same optical and therapeutic properties as the original microbubble, which can be used simultaneously for imaging and drug delivery.

Lipid nanoparticles (LNPs) delivering mRNA after intratumoral administration could be a promising cancer treatment strategy. Here this group reports the intratumoral delivery of mRNA with LNPs inducing the expression of purine nucleoside phosphorylase and inhibiting the progression of head and neck squamous cell carcinoma in vivo.

Cadherin is essential for mechanotransduction and myosin-adaptor-harmonin complexes anchor it to actin. Here the authors present the structures of myosin 7 MF2 domains bound to the harmonin PDZ3c domain and give insights into myosin-adaptor-harmonin complex assembly.

The mucus layer is an important physical niche within the gut which harbours a distinct microbial community. Here the authors show that specific carbohydrate-binding modules associated with bacterial carbohydrate-active enzymes are mucus adhesins that target regions of the distal colon rich in sialomucins.

ONECUT2 is a targetable transcription factor that antagonizes androgen receptor signaling and drives androgen independence and neuroendocrine differentiation in castration-resistant prostate cancer.

Mutations in PCDH15 cause deafness and blindness in Usher syndrome 1 F, but gene therapy is difficult because the PCDH15 sequence is too large for AAV vectors. Here, the authors engineered a miniPCDH15 that fits in AAV and rescues hearing in mouse Usher syndrome 1F models.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be lengthened or shortened by changing the length of the monomers. Now a systematic approach to generate modular repeat protein oligomers with combined symmetry that can be extended by repeat propagation has been developed.

Sexual reproduction in eukaryotes involves gamete fusion, mediated by fusogenic proteins. Here, the authors identify fusogenic protein homologs encoded within mobile genetic elements in archaeal genomes, solve the crystal structure of one of the proteins, and show that its ectopic expression can fuse mammalian cells, suggesting potential roles in cell-cell fusion and gene exchange.

Here the authors develop a ferritin-based protein nanoparticle vaccine candidate for SARS-CoV-2, and show induction of neutralizing antibodies to variants of concern, including Omicron BQ.1, in non-human primates after initial immunization and a booster dose.

Two de novo designed protein classes that link phosphorylation by tyrosine and serine kinases to protein-protein association provide potential new avenues to regulating cell function.

The trRosetta neural network was used to iteratively optimise model proteins from random 100-amino-acid sequences, resulting in ‘hallucinated’ proteins, which when expressed in bacteria closely resembled the model structures.

The high-resolution cryo-electron microscopy structure of a pre-fusion coronavirus spike trimer from mouse hepatitis virus is presented; the structure reveals architectural similarities to paramyxovirus F proteins, suggesting that these fusion proteins may have evolved from a distant common ancestor.

The Alzheimer protein Tau interacts with biological membranes, but the role of these interactions in regulating Tau function in health and disease remains unexplored. Here, the authors report on the discovery and characterization of neurotoxic oligomeric protein/phospholipid complexes.

Computational protein design methods are used to generate new candidates for a human respiratory syncytial virus (RSV) vaccine; artificial protein scaffolds that mimic the structure of a RSV epitope are shown to induce RSV-specific neutralizing antibodies in macaques.

Lipins need to bind cell membranes before they can function as phosphatidic acid phosphatases. Here, the authors elucidate the structural basis of lipin membrane-association and identify a lipin domain with a novel protein fold that is critical for membrane binding and full functionality of lipins.