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Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1 and GGTase2. Here we report the identification of a previously unknown human prenyltransferase complex consisting of an orphan prenyltransferase α-subunit, PTAR1, and the catalytic β-subunit of GGTase2, RabGGTB. This enzyme, which we named GGTase3, geranylgeranylates FBXL2 to allow its localization at cell membranes, where this ubiquitin ligase mediates the polyubiquitylation of membrane-anchored proteins. In cells, FBXL2 is specifically recognized by GGTase3 despite having a typical carboxy-terminal CaaX prenylation motif that is predicted to be recognized by GGTase1. Our crystal structure analysis of the full-length GGTase3–FBXL2–SKP1 complex reveals an extensive multivalent interface specifically formed between the leucine-rich repeat domain of FBXL2 and PTAR1, which unmasks the structural basis of the substrate-enzyme specificity. By uncovering a missing prenyltransferase and its unique mode of substrate recognition, our findings call for a revision of the ‘prenylation code’.

The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.

Preconception and interconception care improves health outcomes of women and communities. Little is known about how prepared and willing Australian midwives are to provide preconception and interconception care. The aim of this study was to explore midwives’ knowledge, perspectives and learning needs, and barriers and enablers to delivering preconception and interconception care. We conducted a cross-sectional exploratory study of midwives working in any Australian maternity setting. An online survey measured midwives’ self-rated knowledge; education needs and preferences; attitudes towards pre and interconception care; and views on barriers, enablers; and, future service and workforce planning. Quantitative data were analysed descriptively and demographic characteristics (e.g., years of experience, model of care) associated with knowledge and attitudes regarding pre- and interconception care were examined using univariate logistic regression analysis. Qualitative data were captured through open-ended questions and analysed using inductive content analysis. We collected responses from ( n = 338) midwives working across all models of care (full survey completion rate 96%). Most participants ( n = 290; 85%) rated their overall knowledge about pre and interconception health as excellent, above average or average. Participants with over 11 years of experience were more likely to report above average to excellent knowledge (OR 3.11; 95% CI 1.09, 8.85). Online e-learning was the most preferred format for education on this topic ( n = 244; 72%). Most ( n = 257; 76%) reported interest in providing pre and interconception care more regularly and that this is within the midwifery scope of practice (n = 292; 87%). Low prioritisation in service planning was the most frequently selected barrier to providing preconception and interconception care, whereas continuity models and hybrid child health settings were reported as enablers of pre and interconception care provision. Findings revealed that midwives are prepared and willing to provide preconception and interconception care. Pre and post registration professional development; service and funding reform; and policy development are critical to enable Australian midwives’ provision of pre and interconception care.

Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in many disease states, including tumour development and progression, there is much interest in understanding the mechanistic basis for how VEGF-A regulates cell and tissue function. VEGF-A binds with high affinity to two VEGF receptor tyrosine kinases (VEGFR1, VEGFR2) and with lower affinity to co-receptors called neuropilin-1 and neuropilin-2 (NRP1, NRP2). Here, we use a structural viewpoint to summarise our current knowledge of VEGF-VEGFR activation and signal transduction. As targeting VEGF-VEGFR activation holds much therapeutic promise, we examine the structural basis for anti-angiogenic therapy using small-molecule compounds such as tyrosine kinase inhibitors that block VEGFR activation and downstream signalling. This review provides a rational basis towards reconciling VEGF and VEGFR structure and function in developing new therapeutics for a diverse range of ailments.

Cardiovascular disease and cancer are major global causes of mortality. Dysfunctional lipid metabolism causes atherosclerosis, a driving force in arterial disease leading to heart attacks and strokes. In this review, we focus on emerging evidence for links between atherosclerosis and cancer. In atherosclerosis, modified and oxidized lipid particles promote plaque initiation and progression, with wider effects on cell and tissue responses. Oxidized and modified lipid particles bind to scavenger receptors (SRs) and promote intracellular signaling and pro-inflammatory responses. Increasing evidence points to SR-mediated activation and signaling promoting cancer cell growth and spread. In particular, the lectin-like oxidized low-density lipoprotein (LOX-1) scavenger receptor activates NF-κB-regulated signal transduction pathways which modulate different cellular responses. LOX-1-regulated signaling events are implicated in both atherosclerosis and cancer, depending on the cell type. LOX-1 signaling modulates cell proliferation, epithelial–mesenchymal transition, neutrophil recruitment and apoptosis. Elevated LOX-1 levels are linked to poor prognosis in arterial disease and prostate, colorectal and lung cancers. Inhibition of LOX-1 function could thus provide new therapeutic strategies for targeting both atherosclerosis and cancer.

The process of atherosclerosis leads to the formation of plaques in the arterial wall, resulting in a decreased blood supply to tissues and organs and its sequelae: morbidity and mortality. A class of membrane-bound proteins termed scavenger receptors (SRs) are closely linked to the initiation and progression of atherosclerosis. Increasing interest in understanding SR structure and function has led to the idea that these proteins could provide new routes for cardiovascular disease diagnosis, management, and treatment. In this review, we consider the main classes of SRs that are implicated in arterial disease. We consider how our understanding of SR-mediated recognition of diverse ligands, including modified lipid particles, lipids, and carbohydrates, has enabled us to better target SR-linked functionality in disease. We also link clinical studies on vascular disease to our current understanding of SR biology and highlight potential areas that are relevant to cardiovascular disease management and therapy.

Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.