MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition.

Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I.

Identification and characterization of nanobodies specific for the human ubiquitin-like ISG15 protein.

Interferon-induced ubiquitin (Ub)-like modifier Interferon Stimulated Gene 15 (ISG15) functions both intracellularly and as a secreted protein with cytokine-like properties. The ISG15 pathway is implicated in various diseases, including cancer and inflammatory disorders, but understanding its precise roles has been challenging because of limited availability of tools to study ISG15 biology. Here, we report the development of two novel nanobodies that target human ISG15, obtained through alpaca immunization and phage display.

Spatiotemporally resolved GPCR interactome uncovers unique mediators of receptor agonism.

Cellular signaling by membrane G protein-coupled receptors (GPCRs) is governed by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome, as it evolves over time and space in response to an agonist, provide a unique perspective on pleiotropic signaling decoding and functional selectivity at the cellular level. In this study, we utilized proximity-based APEX2 proteomics to investigate the interaction network of the luteinizing hormone receptor (LHR) on a minute-to-minute timescale.

Affinity-based protein profiling of MDM2 inhibitor Navtemadlin.

Navtemadlin is a potent inhibitor of the p53-MDM2 protein-protein interaction, which plays a critical role in the proliferation of p53-wildtype tumours. Whilst Navtemadlin has progressed to multiple Phase III clinical trials in oncology, little has been disclosed regarding its selectivity for MDM2 in cells. Here, we report the synthesis and validation of photoactivatable clickable probes of Navtemadlin, and their application to target discovery for Navtemadlin through affinity-based protein profiling.

Advancing Albumin Isolation from Human Serum with Graphene Oxide and Derivatives: A Novel Approach for Clinical Applications.

This study introduces a novel, environmentally friendly albumin isolation method using graphene oxide (GO). GO selectively extracts albumin from serum samples, leveraging the unique interactions between GO's oxygen-containing functional groups and serum proteins. This method achieves high purification efficiency without the need for hazardous chemicals.

A palmitoyl transferase chemical-genetic system to map ZDHHC-specific S-acylation.

The 23 human zinc finger Asp-His-His-Cys motif-containing (ZDHHC) S-acyltransferases catalyze long-chain S-acylation at cysteine residues across an extensive network of hundreds of proteins important for normal physiology or dysregulated in disease. Here we present a technology to directly map the protein substrates of a specific ZDHHC at the whole-proteome level, in intact cells. Structure-guided engineering of paired ZDHHC 'hole' mutants and 'bumped' chemically tagged fatty acid probes enabled probe transfer to specific protein substrates with excellent selectivity over wild-type ZDHHCs.

Salivary peptidome analysis and protease prediction during orthodontic treatment with fixed appliances.

Orthodontic tooth movement (OTM) occurs through proteolytic remodelling within the periodontium following the application of external force to the tooth. This study describes the first characterization of the salivary peptidome and protease profile during the alignment stage of fixed appliance orthodontic treatment. Unstimulated whole mouth saliva from 16 orthodontic patients (10 males, 6 females, mean (SD) age 15.

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia.

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo.

Native chemical ligation approach to sensitively probe tissue acyl-CoA pools.

During metabolism, carboxylic acids are often activated by conjugation to the thiol of coenzyme A (CoA). The resulting acyl-CoAs comprise a group of ∼100 thioester-containing metabolites that could modify protein behavior through non-enzymatic N-acylation of lysine residues. However, the importance of many potential acyl modifications remains unclear because antibody-based methods to detect them are unavailable and the in vivo concentrations of their respective acyl-CoAs are poorly characterized.

Comparative Cell Surface Proteomic Analysis of the Primary Human T Cell and Monocyte Responses to Type I Interferon.

The cellular response to interferon (IFN) is essential for antiviral immunity, IFN-based therapy and IFN-related disease. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Nonetheless, the effect of IFN on PM proteins is surprisingly poorly understood, and has not been systematically investigated in primary immune cells.

ABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex.

2-oxoglutarate (2-OG or α-ketoglutarate) relates mitochondrial metabolism to cell function by modulating the activity of 2-OG dependent dioxygenases involved in the hypoxia response and DNA/histone modifications. However, metabolic pathways that regulate these oxygen and 2-OG sensitive enzymes remain poorly understood. Here, using CRISPR Cas9 genome-wide mutagenesis to screen for genetic determinants of 2-OG levels, we uncover a redox sensitive mitochondrial lipoylation pathway, dependent on the mitochondrial hydrolase ABHD11, that signals changes in mitochondrial 2-OG metabolism to 2-OG dependent dioxygenase function.

Agonists of Orally Expressed TRP Channels Stimulate Salivary Secretion and Modify the Salivary Proteome.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated.

Insights into herpesvirus assembly from the structure of the pUL7:pUL51 complex.

Herpesviruses acquire their membrane envelopes in the cytoplasm of infected cells via a molecular mechanism that remains unclear. Herpes simplex virus (HSV)-1 proteins pUL7 and pUL51 form a complex required for efficient virus envelopment. We show that interaction between homologues of pUL7 and pUL51 is conserved across human herpesviruses, as is their association with -Golgi membranes.

Differences in the Natural Enamel Surface and Acquired Enamel Pellicle following Exposure to Citric or Hydrochloric Acid.

Objectives: The aim of this study was to investigate variations in the interaction between enamel, that is, the acquired enamel pellicle (AEP) and citric or hydrochloric acid.

Materials And Methods: A 24-h AEP was formed on natural enamel specimens (n = 40) from pooled whole mouth human saliva. Samples were randomly allocated to citric (0.

Sensory effects of transient receptor potential channel agonists on whole mouth saliva extensional rheology.

Unlabelled: The extensional rheology (ER) of saliva is a property associated with its ability to coat surfaces and is important for the maintenance of a normal mouth feeling. Transient receptor potential (TRP) channels are expressed in the oral cavity and this study investigated how the sensory effects of TRP channel agonists modify the ER of saliva. Healthy volunteers rinsed with solutions containing a TRP agonist.