Articles

A discovery pipeline integrating time-resolved HT-SAXS and fragment screening identifies chemical leads targeting exemplary allosteric states of mitochondrial oxidoreductase apoptosis-inducing factor (AIF).

A small-molecule iron mobilizer, FeM-1269, minimally higher-order aggregates in aqueous media and effectively mobilizes iron across a range of concentrations. FeM-1269-promoted iron mobilization restores physiology in animals at well-tolerated doses.

A tailored proteomics workflow to identify endogenous protein pyrophosphorylation in human cells was developed, revealing the dependence of the modification on inositol pyrophosphates and a putative function in rDNA transcription.

Cryo-electron microscopy (cryo-EM), kinetic analysis and single-molecule biochemistry reveal how the tubulin tyrosine ligase-like 6 (TTLL6) glutamylase binds reads microtubule geometry and modification state of neighboring tubulins, enabling a spatial positive feedback loop for microtubule modification.

Calcium signals are typically traced through electrophysical, optical and genetic methods. Here the authors report the development of Cal-ID, a calcium-dependent protein proximity labeling tool that can be used to record elevated calcium levels in cells.

The mechanisms of stalled fork degradation in BRCA1/2-deficient cells remain unclear. UFL1, an UFM1-specific E3 ligase, was found to catalyze PTIP UFMylation at lysine 148, promoting stalled fork degradation by the MRE11 nuclease.

Developing disease-modifying drugs for neurodegenerative diseases has been very challenging. Now a machine learning approach has been used to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies. Compounds that bind to the catalytic sites on the surface of the aggregates were identified and then progressively optimized into secondary nucleation inhibitors.

Through rational engineering of A3A deaminase, Yang and colleagues have designed CBEs termed haA3A-CBEs, which feature a condensed editing window and minimal off-target effects that are independent of defined sequence contexts and methylation status.

TERT was dephosphorylated by the protein phosphatase activity of the gluconeogenic enzyme FBP1, leading to inhibition of TERT nuclear translocation and telomere function. Lipid nanoparticle-delivered FBP1 mRNA blunts tumor growth in mice.

A proteomics and computational approach was developed to map the proximal proteome of the activated μ-opioid receptor and to extract subcellular location, trafficking and functional partners of G-protein-coupled receptor activity.

Exportin-1 (XPO1) was identified as the target of small molecules suppressing T cell activation. Selective disruption of the chromatin scaffolding function of XPO1 without blocking nuclear export implicates XPO1 as a target in autoimmunity.

Wenzell et al. developed a massively parallel screening platform to interrogate the sensitivity of signal peptides (SPs) to Sec61 inhibitors. The platform revealed how distinct inhibitors achieve sequence-dependent SP discrimination.

Huang et al. developed E3-substrate tagging by ubiquitin biotinylation (E-STUB), a proximity labeling-based method for direct identification of ubiquitylated substrates for a given E3 ligase, providing a useful tool for substrate discovery of targeted protein degradation and the understanding of E3 ligase function.

Hypoxia induces ·NO-dependent hydrogen sulfide (H₂S) biogenesis by inhibiting the transsulfuration pathway. H₂S oxidation promotes endothelial cell proliferation to support neovascularization in tissue injury and tumor xenograft models.

An approach to design proteins that can capture amyloidogenic protein regions present in, for example, tau and Aβ42 has now been developed. These designer proteins can inhibit the formation of pathogenic amyloid fibrils and protect cells from toxic species.

A method called MEDUSA was developed for identifying death regulatory genes in chemo-genetic profiling data, which enables characterization of a previously unappreciated mechanism of death induced by DNA damage in p53-deficient cells.

The study demonstrates that specific recognition and custom binding geometries can be computationally encoded between protein spans within lipids through designing synthetic transmembrane proteins to functionally regulate a target cytokine receptor.

NMR and Raman spectroscopies pinpoint the role of the protein droplet surface and RNA in the liquid droplet maturation mechanism of the FUS protein. A crust-like β-sheet structure is formed on the surface of FUS droplets during aging.

Yang et al. reported the development of nongenetically engineered artificial mechanoreceptors capable of reprogramming non-mechanoresponsive receptors to sense user-defined force cues, enabling de novo-designed mechanotransduction.

Aerobic glycolysis is a hallmark of fast-growing cells, but it is unclear whether glycolysis was selected for its speed. Glycolysis produces ATP slower than respiration (per protein mass) and is beneficial for rendering cells robust to hypoxia.