Reviews & Analysis

Cells contain compartments composed of phase-separated protein condensates. We find that these condensates have a unique chemical microenvironment that enriches amphipathic metabolites such as phospholipids. Therefore, condensates are mixtures of proteins, nucleic acids and specific metabolites. The presence of phospholipids and other amphipathic metabolites might enable condensates to facilitate specific metabolic reactions.

Controlled interactions between macromolecules are fundamental regulatory layers. Hijacking these circuits via proximity-inducing small molecules offers many therapeutic opportunities. The organizers, Georg Winter and Cristina Mayor-Ruiz, report on the latest trends in this emerging field discussed at the 39th IRB-BioMed Conference in Barcelona.

Terpenoids bearing carbon skeletons derived from nonisoprene units are rare and considered noncanonical. Now, a genome-mining study has uncovered previously unknown noncanonical C₁₆ terpenes and their biosynthetic pathways from bacteria. The findings suggest that noncanonical terpenoids are diverse and widespread in nature.

The integrated stress response affects cell survival or death under stress conditions, and depends on the activity of the eukaryotic translation initiation factor eIF2B. New research identifies a protein helix that modulates this response by controlling the structural states of eIF2B.

LIS1 is an essential cofactor for the assembly of the cytoplasmic dynein transport machinery. How LIS1 binding affects dynein motility was unclear. Single-molecule experiments reveal that Pac1 (the yeast homolog of LIS1) binding reduces dynein speed by slowing its detachment from microtubules and does not disrupt the mechanism by which it generates force.

DNA-encoded libraries are a powerful tool to identify novel chemical inducers of proximity such as targeted protein degraders, even without a known binder for the target protein.

Defining subcellular locations and interacting partners for proteins accelerates their functional characterization. A new in vivo tagging approach achieves both for mitochondrial matrix proteins and helps connect a key oxidoreductase to coenzyme Q biosynthesis.

Genetically encoded tools to manipulate redox metabolism are in high demand for investigating the underlying mechanism of cofactor imbalances in mammalian systems. A new tool enables the induction and interrogation of NADH reductive stress.

Traditional production of therapeutic secretory proteins often experiences delays between protein synthesis and therapeutic effects. An inducible protease-dependent protein secretion technique allows the immediate secretion of pre-translated biotherapeutic agents after exposure to chemical cues, tumor-specific antigens or photons.

We developed a versatile lipid probe — MAO–SiR — to visualize the structure and dynamics of the inner mitochondrial membrane (IMM). MAO–SiR assembles in situ from two cell-permeant small molecules to image the IMM selectively, continuously and at super resolution for extended periods of time without extensive photobleaching or toxicity.

The quality of chemical tools and their appropriate use determine the quality and reliability of scientific data based on their use. Now, two papers extend criteria to new modalities and critically review adherence to established guidelines.

Activation of STING-dependent signal transduction results in adaptive immune responses that promote antitumor immunity. A recent study has identified a small-molecule STING agonist that functions by binding to a newly discovered ligandable site to induce high-order STING oligomerization.

Computational approaches are emerging as powerful tools for the discovery of antibiotics. A study now uses machine learning to discover abaucin, a potent antibiotic that targets the bacterial pathogen Acinetobacter baumannii.

Protein lipidation is an important post-translational modification that can be difficult to study. New amino acids with side chains that mimic naturally occurring lipid modifications stand to facilitate the study of lipidated proteins.

Membrane-less organelles formed by liquid–liquid phase separation provide additional cellular compartmentalization for precise spatiotemporal regulation of biological processes. Ke Ruan, Yi Lin, Peiguo Yang and Wen Zhou report on the formation, regulation and function of biomolecular condensates, discussed at the 2023 Xiangshan Science Conference on Membrane-less Organelles.

The susceptibility of nitric oxide (NO) to scavenging and oxidation limits its bioavailability and signaling role. New studies indicate that a NO–ferroheme adduct is resistant to such constraints and may serve as an alternative NO-derived signaling molecule in vasculature.

By investigating the structure–activity relationship of molecular glue degraders that target cyclin K, we discovered that a wide range of compounds, including known kinase inhibitors, possess this gain-of-function activity. These findings provide insights that might enable more rational design and optimization of molecular glue compounds.

Newly developed synthetic antibodies offer the means to be used as high-affinity, conformation-specific probes to capture dynamic repertoires of neddylated cullin–RING E3 ligase complexes. This allows nonenzymatic profiling of the diverse signaling networks that are based on these active complexes.

CAG triple-nucleotide repeats in multiple genes have been linked to various human diseases. A recent study unveils the effects of CAG repeat RNA gelation on protein translation, thereby expanding our knowledge of CAG-elicited toxicities.