Multisite phosphorylation dictates selective E2-E3 pairing as revealed by Ubc8/UBE2H-GID/CTLH assemblies.

Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH E3 ubiquitin ligases and their dedicated E2, Ubc8/UBE2H (yeast/human nomenclature). GID/CTLH-Ubc8/UBE2H-mediated ubiquitylation regulates biological processes ranging from yeast metabolic signaling to human development.

Body mass index trajectories and their predictors in undergraduate students from Canada: Results from the GENEiUS study.

To explore the patterns and predictors of body mass index (BMI) change among undergraduate students from Ontario (Canada). 68 undergraduate students were followed longitudinally for 3 years with anthropometric data collected bi-annually. BMI measurements were plotted to generate individual BMI trajectory curves, which were categorized, based on the observed trajectory pattern.

A GID E3 ligase assembly ubiquitinates an Rsp5 E3 adaptor and regulates plasma membrane transporters.

Cells rapidly remodel their proteomes to align their cellular metabolism to environmental conditions. Ubiquitin E3 ligases enable this response, by facilitating rapid and reversible changes to protein stability, localization, or interaction partners. In Saccharomyces cerevisiae, the GID E3 ligase regulates the switch from gluconeogenic to glycolytic conditions through induction and incorporation of the substrate receptor subunit Gid4, which promotes the degradation of gluconeogenic enzymes.

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme.

How are E3 ubiquitin ligases configured to match substrate quaternary structures? Here, by studying the yeast GID complex (mutation of which causes deficiency in glucose-induced degradation of gluconeogenic enzymes), we discover supramolecular chelate assembly as an E3 ligase strategy for targeting an oligomeric substrate. Cryoelectron microscopy (cryo-EM) structures show that, to bind the tetrameric substrate fructose-1,6-bisphosphatase (Fbp1), two minimally functional GID E3s assemble into the 20-protein Chelator-GID, which resembles an organometallic supramolecular chelate. The Chelator-GID assembly avidly binds multiple Fbp1 degrons so that multiple Fbp1 protomers are simultaneously ubiquitylated at lysines near the allosteric and substrate binding sites.

Effect of sex/gender on obesity traits in Canadian first year university students: The GENEiUS study.

Background: While weight gain during first year of university has been well documented in North America, literature on sex-specific effects is scarce and inconsistent. The objective of this investigation was to explore sex-specific changes in obesity traits during first year of university at McMaster University (Ontario, Canada).

Methods: 245 first-year students (80.

DIA-based systems biology approach unveils E3 ubiquitin ligase-dependent responses to a metabolic shift.

The yeast is a powerful model system for systems-wide biology screens and large-scale proteomics methods. Nearly complete proteomics coverage has been achieved owing to advances in mass spectrometry. However, it remains challenging to scale this technology for rapid and high-throughput analysis of the yeast proteome to investigate biological pathways on a global scale.

Engaging patients as partners in a multicentre trial of spinal versus general anaesthesia for older adults.

Engaging patients-defined broadly as individuals with lived experience of a given condition, family members, caregivers, and the organisations that represent them-as partners in research is a priority for policymakers, funders, and the public. Nonetheless, formal efforts to engage patients are absent from most studies, and models to support meaningful patient engagement in clinical anaesthesia research have not been previously described. Here, we review our experience in developing and implementing a multifaceted patient engagement strategy within the Regional Versus General Anesthesia for Promoting Independence After Hip Fracture (REGAIN) surgery trial, an ongoing randomised trial comparing spinal vs general anaesthesia for hip fracture surgery in 1600 older adults across 45 hospitals in the USA and Canada.

The effect of race/ethnicity on obesity traits in first year university students from Canada: The GENEiUS study.

Background: Little is known about the impact of race/ethnicity on weight change at university. The objective of this study is to determine if ethnicity has an impact on obesity traits in a multiethnic cohort of first-year students at McMaster University in Ontario, Canada.

Methods: 183 first year students from the three most represented ethnic groups (South Asian, East Asian, and white-Caucasian) in our study sample were followed longitudinally with data collected early in the academic year and towards the end of the year.

Effect of living arrangement on anthropometric traits in first-year university students from Canada: The GENEiUS study.

Background: The transition to university often involves a change in living arrangement for many first-year students. While weight gain during first year of university has been well documented, Canadian literature on the impact of living arrangement within this context is limited. The objective of this investigation was to explore the effect of living arrangement on anthropometric traits in first-year university students from Ontario, Canada.

Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly.

Cells respond to environmental changes by toggling metabolic pathways, preparing for homeostasis, and anticipating future stresses. For example, in Saccharomyces cerevisiae, carbon stress-induced gluconeogenesis is terminated upon glucose availability, a process that involves the multiprotein E3 ligase GID recruiting N termini and catalyzing ubiquitylation of gluconeogenic enzymes. Here, genetics, biochemistry, and cryoelectron microscopy define molecular underpinnings of glucose-induced degradation.

Rationale and design of GENEiUS: a prospective observational study on the genetic and environmental determinants of body mass index evolution in Canadian undergraduate students.

Introduction: Obesity is a global epidemic and is a risk factor for developing other comorbidities. Young adulthood is a critical period for body weight change and establishing healthy lifestyle behaviours. The 'Freshman 15' suggests that undergraduate students gain 15 lbs (6.

Digesting cytotoxic stressors - an unconventional mechanism to induce autophagy.

Autophagy is an essential and fundamental pathway that clears unwanted or damaged material from the cell. Initiation of autophagy was previously shown to be dependent on the Ulk1/2 kinase complex. In this issue of The FEBS Journal, Braden and Neufeld investigated the Ulk3 homolog in Drosophila, and proposed a novel, Ulk1/2 independent pathway for autophagy initiation.

Distinct Prion Domain Sequences Ensure Efficient Amyloid Propagation by Promoting Chaperone Binding or Processing In Vivo.

Prions are a group of proteins that can adopt a spectrum of metastable conformations in vivo. These alternative states change protein function and are self-replicating and transmissible, creating protein-based elements of inheritance and infectivity. Prion conformational flexibility is encoded in the amino acid composition and sequence of the protein, which dictate its ability not only to form an ordered aggregate known as amyloid but also to maintain and transmit this structure in vivo.

Evaluating the transferability of 15 European-derived fasting plasma glucose SNPs in Mexican children and adolescents.

Genome wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) that are associated with fasting plasma glucose (FPG) in adult European populations. The contribution of these SNPs to FPG in non-Europeans and children is unclear. We studied the association of 15 GWAS SNPs and a genotype score (GS) with FPG and 7 metabolic traits in 1,421 Mexican children and adolescents from Mexico City.

Spatial quality control bypasses cell-based limitations on proteostasis to promote prion curing.

The proteostasis network has evolved to support protein folding under normal conditions and to expand this capacity in response to proteotoxic stresses. Nevertheless, many pathogenic states are associated with protein misfolding, revealing in vivo limitations on quality control mechanisms. One contributor to these limitations is the physical characteristics of misfolded proteins, as exemplified by amyloids, which are largely resistant to clearance.

FMRP targets distinct mRNA sequence elements to regulate protein expression.

Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP.

P2Y2 receptor transcription is increased by NF-kappa B and stimulates cyclooxygenase-2 expression and PGE2 released by intestinal epithelial cells.

Inflammatory stresses associated with inflammatory bowel diseases up-regulate P2Y(2) mRNA receptor expression in the human colon adenocarcinoma cell line Caco-2, the noncancerous IEC-6 cells and in colonic tissues of patient suffering from Crohn's disease and ulcerative colitis. However, the transcriptional events regulating P2Y(2) receptor (P2Y(2)R) expression are not known. We have identified a putative transcription start site in the P2Y(2)R gene and demonstrated acetylation of Lys(14) on histone H3 and Lys(8) on histone H4, thus suggesting that the chromatin associated with the P2Y(2) promoter is accessible to transcription factors.

Promoting MPhi transepithelial migration by stimulating the epithelial cell P2Y(2) receptor.

In intestine, neutrophils are recruited in response to bacterial infiltration and their anti-cellular activities contribute to inflammatory bowel diseases. In contrast, little is known regarding the recruitment of MPhi to the intestinal epithelium. Extracellular adenosine and uridine 5'-triphosphate (ATP and UTP) can function as leukocyte chemoattractants.

Intestinal inflammation increases the expression of the P2Y6 receptor on epithelial cells and the release of CXC chemokine ligand 8 by UDP.

Epithelial cells participate in the immune response of the intestinal mucosa. Extracellular nucleotides have been recognized as inflammatory molecules. We investigated the role of extracellular nucleotides and their associated P2Y receptors in the secretion of cytokines by epithelial cells.