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Traffic (Copenhagen, Denmark) Dec 2021Endoplasmic reticulum (ER)-to-Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex-II (COPII) arm of the trafficking... (Review)
Review
Endoplasmic reticulum (ER)-to-Golgi trafficking is an essential and highly conserved cellular process. The coat protein complex-II (COPII) arm of the trafficking machinery incorporates a wide array of cargo proteins into vesicles through direct or indirect interactions with Sec24, the principal subunit of the COPII coat. Approximately one-third of all mammalian proteins rely on the COPII-mediated secretory pathway for membrane insertion or secretion. There are four mammalian Sec24 paralogs and three yeast Sec24 paralogs with emerging evidence of paralog-specific cargo interaction motifs. Furthermore, individual paralogs also differ in their affinity for a subset of sorting motifs present on cargo proteins. As with many aspects of protein trafficking, we lack a systematic and thorough understanding of the interaction of Sec24 with cargoes. This systematic review focuses on the current knowledge of cargo binding to both yeast and mammalian Sec24 paralogs and their ER export motifs. The analyses show that Sec24 paralog specificity of cargo (and cargo receptors) range from exclusive paralog dependence or preference to partial redundancy. We also discuss how the Sec24 secretion system is hijacked by viral (eg, VSV-G, Hepatitis B envelope protein) and bacterial (eg, the enteropathogenic Escherichia coli type III secretion system effector NleA/EspI) pathogens.
Topics: Animals; COP-Coated Vesicles; Endoplasmic Reticulum; Golgi Apparatus; Mammals; Membrane Proteins; Protein Transport; Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Secretory Pathway
PubMed: 34533884
DOI: 10.1111/tra.12817 -
Annual Review of Biochemistry Jun 2021Microorganisms contend with numerous and unusual chemical threats and have evolved a catalog of resistance mechanisms in response. One particularly ancient, pernicious... (Review)
Review
Microorganisms contend with numerous and unusual chemical threats and have evolved a catalog of resistance mechanisms in response. One particularly ancient, pernicious threat is posed by fluoride ion (F), a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways. This review focuses on advances in the last ten years toward understanding the microbial response to cytoplasmic accumulation of F, with a special emphasis on the structure and mechanisms of the proteins that microbes use to export fluoride: the CLC family of F/H antiporters and the Fluc/FEX family of F channels.
Topics: Antiporters; Chloride Channels; Cytoplasm; Fluorides; Ion Channels; Ion Transport; Membrane Proteins; Protein Conformation; Saccharomyces cerevisiae Proteins
PubMed: 33492991
DOI: 10.1146/annurev-biochem-071520-112507 -
Cells Oct 2020During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and... (Review)
Review
During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.
Topics: Animals; Constitutive Androstane Receptor; Endocrine Disruptors; Humans; Inactivation, Metabolic; Liver; Metabolic Networks and Pathways; Mice; Rats; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Xenobiotics
PubMed: 33076503
DOI: 10.3390/cells9102306 -
Journal of Molecular Endocrinology Jan 2021Discovered as a b-ZIP transcription repressor 30 years ago, E4 promoter-binding protein 4 (E4BP4) has been shown to play critical roles in immunity, circadian rhythms,... (Review)
Review
Discovered as a b-ZIP transcription repressor 30 years ago, E4 promoter-binding protein 4 (E4BP4) has been shown to play critical roles in immunity, circadian rhythms, and cancer progression. Recent research has highlighted E4BP4 as a novel regulator of metabolisms in various tissues. In this review, we focus on the function and mechanisms of hepatic E4BP4 in regulating lipid and glucose homeostasis, bile metabolism, as well as xenobiotic metabolism. Finally, E4BP4-specific targets will be discussed for the prevention and treatment of metabolic disorders.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Bile Acids and Salts; Cell Nucleus; Energy Metabolism; Glucose; Humans; Insulin; Lipid Metabolism; Liver
PubMed: 33434146
DOI: 10.1530/JME-20-0239 -
Journal of Thrombosis and Haemostasis :... Nov 2020Protein S is a critical regulator of coagulation that functions as a cofactor for the activated protein C (APC) and tissue factor pathway inhibitor (TFPI) pathways. It... (Review)
Review
Protein S is a critical regulator of coagulation that functions as a cofactor for the activated protein C (APC) and tissue factor pathway inhibitor (TFPI) pathways. It also has direct anticoagulant functions, inhibiting the intrinsic tenase and prothrombinase complexes. Through these functions, protein S regulates coagulation during both its initiation and its propagation phases. The importance of protein S in hemostatic regulation is apparent from the strong association between protein S deficiencies and increased risk for venous thrombosis. This is most likely because both APC and TFPIα are inefficient anticoagulants in the absence of any cofactors. The detailed molecular mechanisms involved in protein S cofactor functions remain to be fully clarified. However, recent advances in the field have greatly improved our understanding of these functions. Evidence suggests that protein S anticoagulant properties often depend on the presence of synergistic cofactors and the formation of multicomponent complexes on negatively charged phospholipid surfaces. Their high affinity binding to negatively charged phospholipids helps bring the anticoagulant proteins to the membranes, resulting in efficient and targeted regulation of coagulation. In this review, we provide an update on protein S and how it functions as a critical hemostatic regulator.
Topics: Anticoagulants; Blood Coagulation; Humans; Protein Binding; Protein S; Protein S Deficiency
PubMed: 32702208
DOI: 10.1111/jth.15025 -
Nucleic Acids Research Jan 2021Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major...
Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
Topics: Bacteria; DNA Methylation; Databases, Factual; Drugs, Investigational; Enzymes; Fungi; Histones; Humans; Inactivation, Metabolic; Internet; Metabolic Clearance Rate; Microbiota; Prescription Drugs; Protein Processing, Post-Translational; RNA, Long Noncoding; Software; Xenobiotics
PubMed: 33045737
DOI: 10.1093/nar/gkaa755 -
Methods in Molecular Biology (Clifton,... 2023Cysteine-SILAC enables the detection and quantification of protein S-palmitoylation, an important protein posttranslational modification. Here we describe the cell...
Cysteine-SILAC enables the detection and quantification of protein S-palmitoylation, an important protein posttranslational modification. Here we describe the cell culture, protein extraction, selective enrichment, mass spectrometry, and data analysis for palmitoylated proteins from cell samples by this method.
Topics: Cysteine; Lipoylation; Mass Spectrometry; Protein Processing, Post-Translational; Proteins
PubMed: 36370270
DOI: 10.1007/978-1-0716-2863-8_5 -
Vitamins and Hormones 2022A wide variety of organisms encode cobalamin-dependent enzymes catalyzing essential metabolic reactions, but the cofactor cobalamin (vitamin B12) is only synthesized by...
A wide variety of organisms encode cobalamin-dependent enzymes catalyzing essential metabolic reactions, but the cofactor cobalamin (vitamin B12) is only synthesized by a subset of bacteria and archaea. The biosynthesis of cobalamin is complex and energetically costly, making cobalamin variants and precursors metabolically valuable. Auxotrophs for these molecules have evolved uptake mechanisms to compensate for the lack of a synthesis pathway. Bacterial transport of cobalamin involves the passage over one or two lipidic membranes in Gram-positive and -negative bacteria, respectively. In higher eukaryotes, a complex system of carriers, receptors and transporters facilitates the delivery of the essential molecule to the tissues. Biochemical and genetic approaches have identified different transporter families involved in cobalamin transport. The majority of the characterized cobalamin transporters are active transport systems that belong to the ATP-binding cassette (ABC) superfamily of transporters. In this chapter, we describe the different cobalamin transport systems characterized to date that are present in bacteria and humans, as well as yet-to-be-identified transporters.
Topics: Biological Transport; Carrier Proteins; Humans; Membrane Transport Proteins; Vitamin B 12
PubMed: 35337617
DOI: 10.1016/bs.vh.2022.01.008 -
Biomolecules Jul 2020Protein post-translational modification (PTM) is a reversible process, which can dynamically regulate the metabolic state of cells through regulation of protein... (Review)
Review
Protein post-translational modification (PTM) is a reversible process, which can dynamically regulate the metabolic state of cells through regulation of protein structure, activity, localization or protein-protein interactions. Actinomycetes are present in the soil, air and water, and their life cycle is strongly determined by environmental conditions. The complexity of variable environments urges Actinomycetes to respond quickly to external stimuli. In recent years, advances in identification and quantification of PTMs have led researchers to deepen their understanding of the functions of PTMs in physiology and metabolism, including vegetative growth, sporulation, metabolite synthesis and infectivity. On the other hand, most donor groups for PTMs come from various metabolites, suggesting a complex association network between metabolic states, PTMs and signaling pathways. Here, we review the mechanisms and functions of PTMs identified in Actinomycetes, focusing on phosphorylation, acylation and protein degradation in an attempt to summarize the recent progress of research on PTMs and their important role in bacterial cellular processes.
Topics: Actinobacteria; Acylation; Bacterial Proteins; Phosphorylation; Protein Processing, Post-Translational; Proteolysis
PubMed: 32751230
DOI: 10.3390/biom10081122 -
Methods in Enzymology 2022A protein's structure and function often depend not only on its primary sequence, but also the presence or absence of any number of non-coded posttranslational...
A protein's structure and function often depend not only on its primary sequence, but also the presence or absence of any number of non-coded posttranslational modifications. Complicating their study is the fact that the physiological consequences of these modifications are context-, protein-, and site-dependent, and there exist no purely biological techniques to unambiguously study their effects. To this end, protein semisynthesis has become an invaluable chemical biology tool to specifically install non-coded or non-native moieties onto proteins in vitro using synthetic and/or recombinant polypeptides. Here, we describe two facets of protein semisynthesis (solid-phase peptide synthesis and expressed protein ligation) and their use in generating site-specifically glycosylated small heat shock proteins for functional studies. The procedures herein require limited specialized equipment, employ mild reaction conditions, and can be extended to myriad other proteins, modifications, and contexts.
Topics: Heat-Shock Proteins, Small; Peptides; Protein Processing, Post-Translational; Proteins
PubMed: 36220281
DOI: 10.1016/bs.mie.2022.07.004