Reviews & Analysis

By combining targetable, cell-permeable photosensitizers with amine-based electrophilic trapping chemistry, a technology termed singlet-oxygen-based photocatalytic proximity labeling (POCA) provides a general strategy for profiling the protein interactomes of diverse molecular baits, including cholesterol, in their native cellular environments.

Biomolecular condensates composed of intrinsically disordered proteins with no inherent catalytic activity promote the reductive amination of diverse metabolites. The proposed electrostatic catalytic mechanism shares features with that used in the active site of enzymes.

How microorganisms build the catalytic heart of the nitrogenase enzyme has remained unknown. Two studies now show how these enzymes repurpose a nitrogenase-like scaffold to assemble the nitrogenase cofactor.

NRF2 enables tumor cells to tolerate oxidative and metabolic stress. A covalent molecular glue restores degradation of NRF2 by stabilizing the KEAP1–ubiquitin ligase complex.

Bowl-shaped mechanosensitive PIEZO channels sense membrane tension by flattening curved transmembrane domains, but how these mechanosensory motions couple with and open the channel pore is unclear. Now, multi-scale molecular dynamics simulations provide insight into this mechano-electrical coupling in PIEZO2, uncovering clockwork-like gating motions of the central pore.

Although long considered to be structured as oligomers comprising a single species, recent work highlights the ability of eukaryotic type 1 peroxiredoxin isoforms to assemble as heterodimers and heterodecamers in vivo. This key property redefines the current understanding of the biological scope of peroxiredoxins.

We used DNA nanostructures to develop nanotraps for the rapid and selective imaging and quantification of norepinephrine (NE) dynamics in subcellular organelles. Using these nanoprobes, we discovered NE bursts in the endoplasmic reticulum (ER) during traumatic brain injury. Increased NE levels in the ER were associated with ER stress, mitochondrial dysfunction and neuronal death.

Understanding protein glycosylation is essential to decode complex cellular networks. A systems-level approach that networks substrate and interacting proteins of O-GlcNAc transferase, the sole enzyme catalyzing O-GlcNAcylation on thousands of proteins, provides insights into the functional relationship of O-GlcNAcylation and coordinated cellular signaling networks.

This study provides a chemical framework of sulfur, defining the cysteine redoxome, linking thiol reactivity with oxoform kinetics/dynamics to proteome-wide mapping, occupancy and flux, and revealing cysteine oxidation as a programmable regulatory code.

Several models have been proposed to explain chromosome segregation during anaphase. By using chemical optogenetics, a study now identifies antiparallel sliding of central spindle microtubules as the driving force of chromosome segregation, while depolymerization of kinetochore microtubules primarily limits spindle elongation.

This Review discusses current research and future directions in protein persulfidation and polysulfidation to enable their full potential in redox-based therapeutic efforts.

The emergence of life is often attributed to an RNA world. Now, it has been shown that mixtures of RNA, peptides and DNA can form coacervate protocells, which possess synergistic properties that can facilitate some of the reactions required for kick-starting life.

Understanding how lipids and proteins interact in living cells is a long-standing challenge. Coupling localized lipid production with proximity proteomics, Tei et al. identified transporters that act on phosphatidic acid. In doing so, they lay out a workflow that could be harnessed for other aspects of membrane homeostasis.

Small molecules that drive ‘neo-protein–protein interactions’ have emerged as an exciting avenue for pharmacological manipulation of protein function. A new entrant in this field inhibits oligomeric proteins by sequestering them into insoluble aggregates.

The interface between biomolecular condensates and cellular membranes underlies many biological processes, yet how biomolecules and lipids reciprocally influence one another’s phase behavior remains poorly understood. A study now shows that membrane composition modulates biomolecular condensation on the membrane, pointing to a new regulatory mechanism of condensation in cells.

Thymine DNA-glycosylase (TDG) has established roles in DNA repair, methylation and transcription, with some implications for cancer development. A study has now identified a synthetic lethality between TDG and p53 in cancer cells, caused by the accumulation of double-stranded RNA.

Ideal efficacy photoswitching is introduced as a concept in controlling protein activity with light. Largely independent of the concentration of a light-responsive compound, it enables TRPC4 and TRPC5 channels to be precisely agonized or antagonized depending on the color of light used.

Activity-based protein profiling facilitated the discovery of complexation state-selective covalent ligands for the pleiotropic methyltransferase adaptor TRMT112. Structural studies revealed that these ligands bind to a pocket at the interface of TRMT112 and METTL5 that is absent in other TRMT112–methyltransferase complexes, resulting in allosteric potentiation of METTL5-mediated rRNA methylation.

Although inhibiting epigenetic enzymes holds strong therapeutic promise, off-target effects remain a prevailing challenge. This study instead targets an accessory reader to fine-tune the inhibitory pathway.

An innovative method to identify ligands for orphan G protein-coupled receptors has been developed using site-specific UV-mediated crosslinking. With this approach, the neuropeptide Little-LEN was identified as an agonist for GPR50, which together regulate energy expenditure in response to metabolic state.