Most cellular membranes are structured as a phospholipid bilayer consisting of two lipid leaflets, and this provides a platform for varied functions including signal transduction, selective transport of molecules, and cell–cell recognition. This issue combines Reviews and Perspectives as well as original research that highlight the evolution of the approaches and conceptual advances in the study of membranes and their component parts, lipids, and proteins.

The cover image depicts the Roman god Janus as having two faces that look to the past and the future and also illustrates the bifunctional nature of the tools used in targeted protein degradation (TPD). This approach utilizes molecular glues or bifunctional compounds to induce stable protein–protein interactions between an endogenous protein of interest and the E3 ubiquitin ligase complex. The collection of pieces in this issue highlights recent research reporting applications of TPD to broader classes of protein targets and for revealing new biological insights.

TAp63α is activated in oocytes with DNA damage to initiate apoptosis through multiple phosphorylation steps mediated by the kinase CK1. Each CK1 phosphorylation step exhibits differential kinetics in which the product of one step also inhibits the next.

See Gebel et al.

Acoustic biosensors, based on genetically encoded air-filled protein nanostructures known as gas vesicles, produce ultrasound signals in response to the action of specific proteases, which allows the activity of these enzymes to be imaged non-invasively inside the body.

See Lakshamanan et al.

Using cell-free protein synthesis and combinatorial pathway assembly in vitro, the iPROBE approach enables rapid generation and screening of engineered biosynthetic pathway ‘cocktails’ to identify and optimize high-performing combinations.

See Karim et al.

The cover depicts conformational dynamics of a short disordered segment of the monomeric yeast prion protein Sup35. This segment modulates the species-specific seeding activity, and a methylene group alone within a side chain of a glutamine residue is sufficient to drastically alter the species specificity of prion transmission.

See Shida et al.

To highlight the occasion of our ‘crystal anniversary’, our cover features a microscopic image of sulfur crystals deposited on a glass surface and visualized with polarized light, which reveals the birefringent properties of the crystal.

See Editorial

Structures of a non-ribosomal depsipeptide synthetase reveal how a pseudoAsub domain, whose sequence is split and separated by intact adenylation and ketoreductase domains, physically reconstitutes itself to enable incorporation of keto acid substrates.

See Alonzo et al

Seeking small proteins. Exploration of translation by combining de novo transcriptome assembly and ribosome profiling illuminated the existence of thousands of previously unannotated small open reading frames that encode microproteins.

See Martinez et al

The bacteria of the human microbiota use bile salt hydrolases (BSHs) to generate dozens of secondary bile acids that can bind to host receptors, including nuclear receptors and G-protein-coupled receptors. A covalent inhibitor generated by appending an electrophile to the sterol core of a bile acid can inhibit all of the BSH activity in rodent microbiota and could prove useful for understanding the effects of bile acids on host physiology.

See Adhikari et al

Seeing both sides. Human pseudouridine synthase Pus10 was found to have two different functions: one is to install pseudouridine modification in tRNAs in a catalytic activity-dependent manner, and the other is to promote miRNA biogenesis in a catalytic-activity-independent manner. The cover depicts two sides of wings pieced together from the same giant blue morpho butterfly symbolizing the dual function of PUS10.

See Song et al

Two bioinformatic tools, BiG-SCAPE and CORASON, enable large-scale analysis of biosynthetic gene clusters and their families across hundreds of bacterial strains and in large datasets, predicting biosynthetic pathways from genomic data and facilitating the discovery of new natural products.

See Navarro-Muñoz et al