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International Journal of Molecular... Jul 2022As the organelle of photosynthesis and other important metabolic pathways, chloroplasts contain up to 70% of leaf proteins with uniquely complex processes in synthesis,... (Review)
Review
As the organelle of photosynthesis and other important metabolic pathways, chloroplasts contain up to 70% of leaf proteins with uniquely complex processes in synthesis, import, assembly, and turnover. Maintaining functional protein homeostasis in chloroplasts is vitally important for the fitness and survival of plants. Research over the past several decades has revealed a multitude of mechanisms that play important roles in chloroplast protein quality control and turnover under normal and stress conditions. These mechanisms include: (i) endosymbiotically-derived proteases and associated proteins that play a vital role in maintaining protein homeostasis inside the chloroplasts, (ii) the ubiquitin-dependent turnover of unimported chloroplast precursor proteins to prevent their accumulation in the cytosol, (iii) chloroplast-associated degradation of the chloroplast outer-membrane translocon proteins for the regulation of chloroplast protein import, (iv) chloroplast unfolded protein response triggered by accumulated unfolded and misfolded proteins inside the chloroplasts, and (v) vesicle-mediated degradation of chloroplast components in the vacuole. Here, we provide a comprehensive review of these diverse mechanisms of chloroplast protein quality control and turnover and discuss important questions that remain to be addressed in order to better understand and improve important chloroplast functions.
Topics: Chloroplast Proteins; Chloroplasts; Photosynthesis; Plants; Protein Transport; Ubiquitin
PubMed: 35887108
DOI: 10.3390/ijms23147760 -
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 -
Nature Structural & Molecular Biology May 2023The challenge of nascent chain folding at the ribosome is met by the conserved ribosome-associated complex (RAC), which forms a chaperone triad with the Hsp70 protein...
The challenge of nascent chain folding at the ribosome is met by the conserved ribosome-associated complex (RAC), which forms a chaperone triad with the Hsp70 protein Ssb in fungi, and consists of the non-canonical Hsp70 Ssz1 and the J domain protein Zuotin (Zuo1). Here we determine cryo-EM structures of Chaetomium thermophilum RAC bound to 80S ribosomes. RAC adopts two distinct conformations accommodating continuous ribosomal rotation by a flexible lever arm. It is held together by a tight interaction between the Ssz1 substrate-binding domain and the Zuo1 N terminus, and additional contacts between the Ssz1 nucleotide-binding domain and Zuo1 J- and Zuo1 homology domains, which form a rigid unit. The Zuo1 HPD motif conserved in J-proteins is masked in a non-canonical interaction by the Ssz1 nucleotide-binding domain, and allows the positioning of Ssb for activation by Zuo1. Overall, we provide the basis for understanding how RAC cooperates with Ssb in a dynamic nascent chain interaction and protein folding.
Topics: Saccharomyces cerevisiae; Protein Binding; Protein Folding; Saccharomyces cerevisiae Proteins; HSP70 Heat-Shock Proteins; Ribosomes; Nucleotides; Molecular Chaperones
PubMed: 37081320
DOI: 10.1038/s41594-023-00973-1 -
The Journal of Clinical Investigation Sep 2021Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors... (Review)
Review
Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the "balanced" proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.
Topics: Active Transport, Cell Nucleus; Databases, Genetic; Humans; Metabolic Networks and Pathways; MicroRNAs; Models, Biological; Mutant Proteins; Mutation; Neoplasm Proteins; Neoplasms; Phenotype; Protein Biosynthesis; RNA Processing, Post-Transcriptional; RNA Splicing; RNA, Neoplasm; RNA-Binding Proteins; Transcription, Genetic
PubMed: 34523614
DOI: 10.1172/JCI151627 -
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 -
FEBS Letters Jul 2023Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and... (Review)
Review
Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post-translational modifications and metabolite-based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.
Topics: Humans; Protein Folding; Molecular Chaperones; HSP90 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Protein Processing, Post-Translational
PubMed: 37287189
DOI: 10.1002/1873-3468.14682 -
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