News & Views

Temperature-sensitive proteins promise precise, remote and penetrant control of cells, but few such proteins are currently available. A study finds that certain existing protein switches can moonlight as thermosensors, immediately expanding the landscape of temperature-sensitive probes.

CenSpark, a dual-ligand fluorescent probe, enables selective live-cell imaging of centriolar and ciliary microtubule doublets and triplets across eukaryotes. By sensing higher-order architecture rather than tubulin alone, it establishes a new paradigm for labeling specialized cytoskeletal assemblies in cells.

Molecular glues offer a promising avenue for novel therapeutic development. The discovery of CLEO4-88 reveals a non-degradative molecular glue that promotes interaction between the CTLH substrate receptor GID4 and the peroxisomal thiolase ACAA1, inhibiting the enzymatic activity of ACAA1.

A study established a photocatalytic proximity interactomic platform tailored to lipid droplets. This platform uses custom photosensitizers to enable in situ labeling, allowing researchers to identify contact sites of lipid droplets with other organelles in living cells without the need for genetic engineering.

Two new studies introduce a high-throughput SuFEx platform and a covalent prodrug strategy that converts target ligands into molecular glues, revealing new E3 ligase candidates for targeted protein degradation.

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.

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.

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.

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.

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.

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.