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Biomolecules, Volume 4, Issue 4 (December 2014), Pages 885-1154

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Research

Jump to: Review

Open AccessArticle Inhibitory Effect of b-AP15 on the 20S Proteasome
Biomolecules 2014, 4(4), 931-939; doi:10.3390/biom4040931
Received: 5 June 2014 / Revised: 5 August 2014 / Accepted: 23 September 2014 / Published: 14 October 2014
Cited by 1 | PDF Full-text (4262 KB) | HTML Full-text | XML Full-text
Abstract
The 26S proteasome is a cellular proteolytic complex containing 19S regulatory particles and the 20S core proteasome. It was reported that the small molecule b-AP15 targets the proteasome by inhibiting deubiquitination of the 19S regulatory particles of the proteasome complex. An investigation of
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The 26S proteasome is a cellular proteolytic complex containing 19S regulatory particles and the 20S core proteasome. It was reported that the small molecule b-AP15 targets the proteasome by inhibiting deubiquitination of the 19S regulatory particles of the proteasome complex. An investigation of b-AP15 on the 20S proteasome core suggested that this compound can also inhibit the 20S proteasome with a potency equivalent to that found to inhibit the 19S regulatory particles. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessArticle Probing the Kinetic Stabilities of Friedreich’s Ataxia Clinical Variants Using a Solid Phase GroEL Chaperonin Capture Platform
Biomolecules 2014, 4(4), 956-979; doi:10.3390/biom4040956
Received: 5 February 2014 / Revised: 29 August 2014 / Accepted: 19 September 2014 / Published: 20 October 2014
Cited by 2 | PDF Full-text (67855 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental
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Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 °C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN-p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich’s ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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Open AccessArticle Long Chain Fatty Acid Acylated Derivatives of Quercetin-3-O-Glucoside as Antioxidants to Prevent Lipid Oxidation
Biomolecules 2014, 4(4), 980-993; doi:10.3390/biom4040980
Received: 9 September 2014 / Revised: 16 October 2014 / Accepted: 27 October 2014 / Published: 6 November 2014
Cited by 3 | PDF Full-text (241 KB) | HTML Full-text | XML Full-text
Abstract
Flavonoids have shown promise as natural plant-based antioxidants for protecting lipids from oxidation. It was hypothesized that their applications in lipophilic food systems can be further enhanced by esterification of flavonoids with fatty acids. Quercetin-3-O-glucoside (Q3G) was esterified individually with six
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Flavonoids have shown promise as natural plant-based antioxidants for protecting lipids from oxidation. It was hypothesized that their applications in lipophilic food systems can be further enhanced by esterification of flavonoids with fatty acids. Quercetin-3-O-glucoside (Q3G) was esterified individually with six selected long chain fatty acids: stearic acid (STA), oleic acid (OLA), linoleic acid (LNA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and decosahexaenoic acid (DHA), using Candida antarctica B lipase as the biocatalyst. The antioxidant activity of esterified flavonoids was evaluated using lipid oxidation model systems of poly-unsaturated fatty acids-rich fish oil and human low density lipoprotein (LDL), in vitro. In the oil-in-water emulsion, Q3G esters exhibited 50% to 100% inhibition in primary oxidation and 30% to 75% inhibition in secondary oxidation. In bulk oil, Q3G esters did not provide considerable protection from lipid oxidation; however, Q3G demonstrated more than 50% inhibition in primary oxidation. EPA, DHA and ALA esters of Q3G showed significantly higher inhibition in Cu2+- and peroxyl radical-induced LDL oxidation in comparison to Q3G. Full article
Open AccessArticle A Facile and Sensitive Method for Quantification of Cyclic Nucleotide Monophosphates in Mammalian Organs: Basal Levels of Eight cNMPs and Identification of 2',3'-cIMP
Biomolecules 2014, 4(4), 1070-1092; doi:10.3390/biom4041070
Received: 8 August 2014 / Revised: 27 November 2014 / Accepted: 1 December 2014 / Published: 12 December 2014
Cited by 3 | PDF Full-text (80068 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A sensitive, versatile and economical method to extract and quantify cyclic nucleotide monophosphates (cNMPs) using LC-MS/MS, including both 3',5'-cNMPs and 2',3'-cNMPs, in mammalian tissues and cellular systems has been developed. Problems, such as matrix effects from complex biological samples, are addressed and have
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A sensitive, versatile and economical method to extract and quantify cyclic nucleotide monophosphates (cNMPs) using LC-MS/MS, including both 3',5'-cNMPs and 2',3'-cNMPs, in mammalian tissues and cellular systems has been developed. Problems, such as matrix effects from complex biological samples, are addressed and have been optimized. This protocol allows for comparison of multiple cNMPs in the same system and was used to examine the relationship between tissue levels of cNMPs in a panel of rat organs. In addition, the study reports the first identification and quantification of 2',3'-cIMP. The developed method will allow for quantification of cNMPs levels in cells and tissues with varying disease states, which will provide insight into the role(s) and interplay of cNMP signalling pathways. Full article
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Open AccessCommunication Microbial Transformation of Bioactive Compounds and Production of ortho-Dihydroxyisoflavones and Glycitein from Natural Fermented Soybean Paste
Biomolecules 2014, 4(4), 1093-1101; doi:10.3390/biom4041093
Received: 16 September 2014 / Revised: 28 November 2014 / Accepted: 3 December 2014 / Published: 12 December 2014
Cited by 2 | PDF Full-text (11036 KB) | HTML Full-text | XML Full-text
Abstract
Recently, there has been a great deal of remarkable interest in finding bioactive compounds from nutritional foods to replace synthetic compounds. In particular, ortho-dihydroxyisoflavones and glycitein are of growing scientific interest owing to their attractive biological properties. In this study, 7,8-
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Recently, there has been a great deal of remarkable interest in finding bioactive compounds from nutritional foods to replace synthetic compounds. In particular, ortho-dihydroxyisoflavones and glycitein are of growing scientific interest owing to their attractive biological properties. In this study, 7,8-ortho-dihydroxyisoflavone, 6,7-ortho-dihydroxyisoflavone, 3',4'-ortho-dihydroxyisoflavone and 7,4'-dihydroxy-6-methoxyisoflavone were characterized using microorganism screened from soybean Doenjang. Three ortho-dihydroxyisoflavones and glycitein were structurally elucidated by 1H-NMR and GC-MS analysis. Furthermore, bacterial strains from soybean Doenjang with the capacity of biotransformation were screened. The bacterial strain, identified as Bacillus subtilis Roh-1, was shown to convert daidzein into ortho-dihydroxyisoflavones and glycitein. Thus, this study has, for the first time, demonstrated that a bacterial strain had a substrate specificity for multiple modifications of the bioactive compounds. Full article

Review

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Open AccessReview Proteasome- and Ethanol-Dependent Regulation of HCV-Infection Pathogenesis
Biomolecules 2014, 4(4), 885-896; doi:10.3390/biom4040885
Received: 29 May 2014 / Revised: 5 August 2014 / Accepted: 16 September 2014 / Published: 29 September 2014
Cited by 4 | PDF Full-text (85 KB) | HTML Full-text | XML Full-text
Abstract
This paper reviews the role of the catabolism of HCV and signaling proteins in HCV protection and the involvement of ethanol in HCV-proteasome interactions. HCV specifically infects hepatocytes, and intracellularly expressed HCV proteins generate oxidative stress, which is further exacerbated by heavy drinking.
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This paper reviews the role of the catabolism of HCV and signaling proteins in HCV protection and the involvement of ethanol in HCV-proteasome interactions. HCV specifically infects hepatocytes, and intracellularly expressed HCV proteins generate oxidative stress, which is further exacerbated by heavy drinking. The proteasome is the principal proteolytic system in cells, and its activity is sensitive to the level of cellular oxidative stress. Not only host proteins, but some HCV proteins are degraded by the proteasome, which, in turn, controls HCV propagation and is crucial for the elimination of the virus. Ubiquitylation of HCV proteins usually leads to the prevention of HCV propagation, while accumulation of undegraded viral proteins in the nuclear compartment exacerbates infection pathogenesis. Proteasome activity also regulates both innate and adaptive immunity in HCV-infected cells. In addition, the proteasome/immunoproteasome is activated by interferons, which also induce “early” and “late” interferon-sensitive genes (ISGs) with anti-viral properties. Cleaving viral proteins to peptides in professional immune antigen presenting cells and infected (“target”) hepatocytes that express the MHC class I-antigenic peptide complex, the proteasome regulates the clearance of infected hepatocytes by the immune system. Alcohol exposure prevents peptide cleavage by generating metabolites that impair proteasome activity, thereby providing escape mechanisms that interfere with efficient viral clearance to promote the persistence of HCV-infection. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Cullin E3 Ligases and Their Rewiring by Viral Factors
Biomolecules 2014, 4(4), 897-930; doi:10.3390/biom4040897
Received: 21 April 2014 / Revised: 20 August 2014 / Accepted: 15 September 2014 / Published: 13 October 2014
Cited by 7 | PDF Full-text (51116 KB) | HTML Full-text | XML Full-text
Abstract
The ability of viruses to subvert host pathways is central in disease pathogenesis. Over the past decade, a critical role for the Ubiquitin Proteasome System (UPS) in counteracting host immune factors during viral infection has emerged. This counteraction is commonly achieved by the
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The ability of viruses to subvert host pathways is central in disease pathogenesis. Over the past decade, a critical role for the Ubiquitin Proteasome System (UPS) in counteracting host immune factors during viral infection has emerged. This counteraction is commonly achieved by the expression of viral proteins capable of sequestering host ubiquitin E3 ligases and their regulators. In particular, many viruses hijack members of the Cullin-RING E3 Ligase (CRL) family. Viruses interact in many ways with CRLs in order to impact their ligase activity; one key recurring interaction involves re-directing CRL complexes to degrade host targets that are otherwise not degraded within host cells. Removal of host immune factors by this mechanism creates a more amenable cellular environment for viral propagation. To date, a small number of target host factors have been identified, many of which are degraded via a CRL-proteasome pathway. Substantial effort within the field is ongoing to uncover the identities of further host proteins targeted in this fashion and the underlying mechanisms driving their turnover by the UPS. Elucidation of these targets and mechanisms will provide appealing anti-viral therapeutic opportunities. This review is focused on the many methods used by viruses to perturb host CRLs, focusing on substrate sequestration and viral regulation of E3 activity. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Nuclear Transport of Yeast Proteasomes
Biomolecules 2014, 4(4), 940-955; doi:10.3390/biom4040940
Received: 2 June 2014 / Revised: 18 August 2014 / Accepted: 26 September 2014 / Published: 20 October 2014
Cited by 6 | PDF Full-text (13375 KB) | HTML Full-text | XML Full-text
Abstract
Proteasomes are conserved protease complexes enriched in the nuclei of dividing yeast cells, a major site for protein degradation. If yeast cells do not proliferate and transit to quiescence, metabolic changes result in the dissociation of proteasomes into proteolytic core and regulatory complexes
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Proteasomes are conserved protease complexes enriched in the nuclei of dividing yeast cells, a major site for protein degradation. If yeast cells do not proliferate and transit to quiescence, metabolic changes result in the dissociation of proteasomes into proteolytic core and regulatory complexes and their sequestration into motile cytosolic proteasome storage granuli. These granuli rapidly clear with the resumption of growth, releasing the stored proteasomes, which relocalize back to the nucleus to promote cell cycle progression. Here, I report on three models of how proteasomes are transported from the cytoplasm into the nucleus of yeast cells. The first model applies for dividing yeast and is based on the canonical pathway using classical nuclear localization sequences of proteasomal subcomplexes and the classical import receptor importin/karyopherin αβ. The second model applies for quiescent yeast cells, which resume growth and use Blm10, a HEAT-like repeat protein structurally related to karyopherin β, for nuclear import of proteasome core particles. In the third model, the fully-assembled proteasome is imported into the nucleus. Our still marginal knowledge about proteasome dynamics will inspire the discussion on how protein degradation by proteasomes may be regulated in different cellular compartments of dividing and quiescent eukaryotic cells. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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Open AccessReview Proteasome Subtypes and Regulators in the Processing of Antigenic Peptides Presented by Class I Molecules of the Major Histocompatibility Complex
Biomolecules 2014, 4(4), 994-1025; doi:10.3390/biom4040994
Received: 30 July 2014 / Revised: 2 October 2014 / Accepted: 29 October 2014 / Published: 18 November 2014
Cited by 15 | PDF Full-text (397 KB) | HTML Full-text | XML Full-text
Abstract
The proteasome is responsible for the breakdown of cellular proteins. Proteins targeted for degradation are allowed inside the proteasome particle, where they are cleaved into small peptides and released in the cytosol to be degraded into amino acids. In vertebrates, some of these
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The proteasome is responsible for the breakdown of cellular proteins. Proteins targeted for degradation are allowed inside the proteasome particle, where they are cleaved into small peptides and released in the cytosol to be degraded into amino acids. In vertebrates, some of these peptides escape degradation in the cytosol, are loaded onto class I molecules of the major histocompatibility complex (MHC) and displayed at the cell surface for scrutiny by the immune system. The proteasome therefore plays a key role for the immune system: it provides a continued sampling of intracellular proteins, so that CD8-positive T-lymphocytes can kill cells expressing viral or tumoral proteins. Consequently, the repertoire of peptides displayed by MHC class I molecules at the cell surface depends on proteasome activity, which may vary according to the presence of proteasome subtypes and regulators. Besides standard proteasomes, cells may contain immunoproteasomes, intermediate proteasomes and thymoproteasomes. Cells may also contain regulators of proteasome activity, such as the 19S, PA28 and PA200 regulators. Here, we review the effects of these proteasome subtypes and regulators on the production of antigenic peptides. We also discuss an unexpected function of the proteasome discovered through the study of antigenic peptides: its ability to splice peptides. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Functions of the Proteasome on Chromatin
Biomolecules 2014, 4(4), 1026-1044; doi:10.3390/biom4041026
Received: 11 August 2014 / Revised: 11 September 2014 / Accepted: 10 November 2014 / Published: 21 November 2014
Cited by 7 | PDF Full-text (15823 KB) | HTML Full-text | XML Full-text
Abstract
The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur
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The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur on chromatin. In this review, we discuss some of the ways in which proteasomes directly regulate the structure and function of chromatin and chromatin regulatory proteins, and how this influences gene transcription. We discuss lingering controversies in the field, the relative importance of proteolytic versus non-proteolytic proteasome activities in this process, and highlight areas that require further investigation. Our intention is to show that proteasomes are involved in major steps controlling the expression of the genetic information, that proteasomes use both proteolytic mechanisms and ATP-dependent protein remodeling to accomplish this task, and that much is yet to be learned about the full spectrum of ways that proteasomes influence the genome. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview The Immunoglobulins of Cold-Blooded Vertebrates
Biomolecules 2014, 4(4), 1045-1069; doi:10.3390/biom4041045
Received: 28 September 2014 / Revised: 10 November 2014 / Accepted: 13 November 2014 / Published: 24 November 2014
Cited by 13 | PDF Full-text (24386 KB) | HTML Full-text | XML Full-text
Abstract
Although lymphocyte-like cells secreting somatically-recombining receptors have been identified in the jawless fishes (hagfish and lamprey), the cartilaginous fishes (sharks, skates, rays and chimaera) are the most phylogenetically distant group relative to mammals in which bona fide immunoglobulins (Igs) have been found. Studies
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Although lymphocyte-like cells secreting somatically-recombining receptors have been identified in the jawless fishes (hagfish and lamprey), the cartilaginous fishes (sharks, skates, rays and chimaera) are the most phylogenetically distant group relative to mammals in which bona fide immunoglobulins (Igs) have been found. Studies of the antibodies and humoral immune responses of cartilaginous fishes and other cold-blooded vertebrates (bony fishes, amphibians and reptiles) are not only revealing information about the emergence and roles of the different Ig heavy and light chain isotypes, but also the evolution of specialised adaptive features such as isotype switching, somatic hypermutation and affinity maturation. It is becoming increasingly apparent that while the adaptive immune response in these vertebrate lineages arose a long time ago, it is most definitely not primitive and has evolved to become complex and sophisticated. This review will summarise what is currently known about the immunoglobulins of cold-blooded vertebrates and highlight the differences, and commonalities, between these and more “conventional” mammalian species. Full article
(This article belongs to the Special Issue Immunoglobulin)
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Open AccessReview Immunoglobulins: 25 Years of Immunoinformatics and IMGT-ONTOLOGY
Biomolecules 2014, 4(4), 1102-1139; doi:10.3390/biom4041102
Received: 5 November 2014 / Revised: 2 December 2014 / Accepted: 3 December 2014 / Published: 16 December 2014
Cited by 5 | PDF Full-text (80077 KB) | HTML Full-text | XML Full-text
Abstract
IMGT®, the international ImMunoGeneTics information system® (CNRS and Montpellier University) is the global reference in immunogenetics and immunoinformatics. By its creation in 1989, IMGT® marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT
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IMGT®, the international ImMunoGeneTics information system® (CNRS and Montpellier University) is the global reference in immunogenetics and immunoinformatics. By its creation in 1989, IMGT® marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT® is specialized in the immunoglobulins (IG) or antibodies, T cell receptors (TR), major histocompatibility (MH), and IgSF and MhSF superfamilies. IMGT® has been built on the IMGT-ONTOLOGY axioms and concepts, which bridged the gap between genes, sequences and three-dimensional (3D) structures. The concepts include the IMGT® standardized keywords (identification), IMGT® standardized labels (description), IMGT® standardized nomenclature (classification), IMGT unique numbering and IMGT Colliers de Perles (numerotation). IMGT® comprises seven databases, 15,000 pages of web resources and 17 tools. IMGT® tools and databases provide a high-quality analysis of the IG from fish to humans, for basic, veterinary and medical research, and for antibody engineering and humanization. They include, as examples: IMGT/V-QUEST and IMGT/JunctionAnalysis for nucleotide sequence analysis and their high-throughput version IMGT/HighV-QUEST for next generation sequencing, IMGT/DomainGapAlign for amino acid sequence analysis of IG domains, IMGT/3Dstructure-DB for 3D structures, contact analysis and paratope/epitope interactions of IG/antigen complexes, and the IMGT/mAb-DB interface for therapeutic antibodies and fusion proteins for immunological applications (FPIA). Full article
(This article belongs to the Special Issue Immunoglobulin)
Open AccessReview Proteins Directly Interacting with Mammalian 20S Proteasomal Subunits and Ubiquitin-Independent Proteasomal Degradation
Biomolecules 2014, 4(4), 1140-1154; doi:10.3390/biom4041140
Received: 1 June 2014 / Revised: 25 November 2014 / Accepted: 11 December 2014 / Published: 19 December 2014
Cited by 4 | PDF Full-text (7351 KB) | HTML Full-text | XML Full-text
Abstract
The mammalian 20S proteasome is a heterodimeric cylindrical complex (α7β7β7α7), composed of four rings each composed of seven different α or β subunits with broad proteolytic activity. We review the mammalian proteins shown to directly interact with specific 20S proteasomal subunits and those
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The mammalian 20S proteasome is a heterodimeric cylindrical complex (α7β7β7α7), composed of four rings each composed of seven different α or β subunits with broad proteolytic activity. We review the mammalian proteins shown to directly interact with specific 20S proteasomal subunits and those subjected to ubiquitin-independent proteasomal degradation (UIPD). The published reports of proteins that interact with specific proteasomal subunits, and others found on interactome databases and those that are degraded by a UIPD mechanism, overlap by only a few protein members. Therefore, systematic studies of the specificity of the interactions, the elucidation of the protein regions implicated in the interactions (that may or may not be followed by degradation) and competition experiments between proteins known to interact with the same proteasomal subunit, are needed. Those studies should provide a coherent picture of the molecular mechanisms governing the interactions of cellular proteins with proteasomal subunits, and their relevance to cell proteostasis and cell functioning. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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