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Biomolecules, Volume 4, Issue 3 (September 2014), Pages 600-884

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Research

Jump to: Review

Open AccessArticle Assembly Mechanisms of Specialized Core Particles of the Proteasome
Biomolecules 2014, 4(3), 662-677; doi:10.3390/biom4030662
Received: 3 April 2014 / Revised: 30 May 2014 / Accepted: 22 June 2014 / Published: 16 July 2014
Cited by 1 | PDF Full-text (2404 KB) | HTML Full-text | XML Full-text
Abstract
The 26S proteasome has a highly complicated structure comprising the 20S core particle (CP) and the 19S regulatory particle (RP). Along with the standard CP in all eukaryotes, vertebrates have two more subtypes of CP called the immunoproteasome and the thymoproteasome. The immunoproteasome
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The 26S proteasome has a highly complicated structure comprising the 20S core particle (CP) and the 19S regulatory particle (RP). Along with the standard CP in all eukaryotes, vertebrates have two more subtypes of CP called the immunoproteasome and the thymoproteasome. The immunoproteasome has catalytic subunits β1i, β2i, and β5i replacing β1, β2, and β5 and enhances production of major histocompatibility complex I ligands. The thymoproteasome contains thymus-specific subunit β5t in place of β5 or β5i and plays a pivotal role in positive selection of CD8+ T cells. Here we investigate the assembly pathways of the specialized CPs and show that β1i and β2i are incorporated ahead of all the other β-subunits and that both β5i and β5t can be incorporated immediately after the assembly of β3 in the absence of β4, distinct from the assembly of the standard CP in which β-subunits are incorporated in the order of β2, β3, β4, β5, β6, β1, and β7. The propeptide of β5t is a key factor for this earlier incorporation, whereas the body sequence seems to be important for the earlier incorporation of β5i. This unique feature of β5t and β5i may account for preferential assembly of the immunoproteasome and the thymoproteasome over the standard type even when both the standard and specialized subunits are co-expressed. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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Open AccessArticle Differential Expression of 26S Proteasome Subunits and Functional Activity during Neonatal Development
Biomolecules 2014, 4(3), 812-826; doi:10.3390/biom4030812
Received: 6 February 2014 / Revised: 2 May 2014 / Accepted: 19 August 2014 / Published: 29 August 2014
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Abstract
Proteasomes regulate many essential cellular processes by degrading intracellular proteins. While aging is known to be associated with dysfunction of the proteasome, there are few reports detailing activity and function of proteasomes in the early stages of life. To elucidate the function and
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Proteasomes regulate many essential cellular processes by degrading intracellular proteins. While aging is known to be associated with dysfunction of the proteasome, there are few reports detailing activity and function of proteasomes in the early stages of life. To elucidate the function and development of mammalian proteasomes, 26S proteasomes were affinity-purified from rat intestine, spleen and liver. The developmental expression of core, regulatory and immunoproteasome subunits was analyzed by immunoblotting and reverse-transcriptase PCR of mRNA subunits, and proteasome catalytic function was determined by fluorogenic enzymatic assays. The expression of core (β2, β5, α7 and β1) and regulatory (Rpt5) subunits was found to be present at low levels at birth and increased over time particularly at weaning. In contrast, while gradual developmental progression of proteasome structure was also seen with the immunoproteasome subunits (β1i, β5i, and β2i), these were not present at birth. Our studies demonstrate a developmental pattern to 26S proteasome activity and subunit expression, with low levels of core proteasome components and absence of immunoproteasomes at birth followed by increases at later developmental stages. This correlates with findings from other studies of a developmental hyporesponsiveness of the adaptive immune system to allow establishment of microbial colonization immediately after birth. Full article

Review

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Open AccessReview Structures and Metal-Binding Properties of Helicobacter pylori Neutrophil-Activating Protein with a Di-Nuclear Ferroxidase Center
Biomolecules 2014, 4(3), 600-615; doi:10.3390/biom4030600
Received: 11 January 2014 / Revised: 3 June 2014 / Accepted: 4 June 2014 / Published: 26 June 2014
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Abstract
Helicobacter pylori causes severe diseases, such as chronic gastritis, peptic ulcers, and stomach cancers. H. pylori neutrophil-activating protein (HP-NAP) is an iron storage protein that forms a dodecameric shell, promotes the adhesion of neutrophils to endothelial cells, and induces the production of reactive
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Helicobacter pylori causes severe diseases, such as chronic gastritis, peptic ulcers, and stomach cancers. H. pylori neutrophil-activating protein (HP-NAP) is an iron storage protein that forms a dodecameric shell, promotes the adhesion of neutrophils to endothelial cells, and induces the production of reactive oxygen radicals. HP-NAP belongs to the DNA-protecting proteins under starved conditions (Dps) family, which has significant structural similarities to the dodecameric ferritin family. The crystal structures of the apo form and metal-ion bound forms, such as iron, zinc, and cadmium, of HP-NAP have been determined. This review focused on the structures and metal-binding properties of HP-NAP. These metal ions bind at the di-nuclear ferroxidase center (FOC) by different coordinating patterns. In comparison with the apo structure, metal loading causes a series of conformational changes in conserved residues among HP-NAP and Dps proteins (Trp26, Asp52, and Glu56) at the FOC. HP-NAP forms a spherical dodecamer with 23 symmetry including two kinds of pores. Metal ions have been identified around one of the pores; therefore, the negatively-charged pore is suitable for the passage of metal ions. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview QM/MM Molecular Dynamics Studies of Metal Binding Proteins
Biomolecules 2014, 4(3), 616-645; doi:10.3390/biom4030616
Received: 18 March 2014 / Revised: 5 June 2014 / Accepted: 6 June 2014 / Published: 8 July 2014
Cited by 17 | PDF Full-text (1502 KB) | HTML Full-text | XML Full-text
Abstract
Mixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have
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Mixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have to be explicitly taken into account for the correct representation of the underlying biochemical process. In this review, after a brief description of the basic concepts of the QM/MM method, we provide an overview of its capabilities using selected examples taken from our work. Specifically, we will focus on heme peroxidases, metallo-β-lactamases, α-synuclein and ligase ribozymes to show how this approach is capable of describing the catalytic and/or structural role played by transition (Fe, Zn or Cu) and main group (Mg) metals. Applications will reveal how metal ions influence the formation and reduction of high redox intermediates in catalytic cycles and enhance drug metabolism, amyloidogenic aggregate formation and nucleic acid synthesis. In turn, it will become manifest that the protein frame directs and modulates the properties and reactivity of the metal ions. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview Protein Quality Control in the Nucleus
Biomolecules 2014, 4(3), 646-661; doi:10.3390/biom4030646
Received: 31 March 2014 / Revised: 20 May 2014 / Accepted: 4 June 2014 / Published: 9 July 2014
Cited by 4 | PDF Full-text (870 KB) | HTML Full-text | XML Full-text
Abstract
In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins
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In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins are prone to aggregate, cells have evolved several elaborate quality control systems to deal with these potentially toxic proteins. First, various molecular chaperones will seize the misfolded protein and either attempt to refold the protein or target it for degradation via the ubiquitin-proteasome system. The degradation of misfolded proteins is clearly compartmentalized, so unique degradation pathways exist for misfolded proteins depending on whether their subcellular localization is ER/secretory, mitochondrial, cytosolic or nuclear. Recent studies, mainly in yeast, have shown that the nucleus appears to be particularly active in protein quality control. Thus, specific ubiquitin-protein ligases located in the nucleus, target not only misfolded nuclear proteins, but also various misfolded cytosolic proteins which are transported to the nucleus prior to their degradation. In comparison, much less is known about these mechanisms in mammalian cells. Here we highlight recent advances in our understanding of nuclear protein quality control, in particular regarding substrate recognition and proteasomal degradation. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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Open AccessReview New Perspectives on Oxidized Genome Damage and Repair Inhibition by Pro-Oxidant Metals in Neurological Diseases
Biomolecules 2014, 4(3), 678-703; doi:10.3390/biom4030678
Received: 29 April 2014 / Revised: 24 June 2014 / Accepted: 25 June 2014 / Published: 17 July 2014
Cited by 8 | PDF Full-text (691 KB) | HTML Full-text | XML Full-text
Abstract
The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome,
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The primary cause(s) of neuronal death in most cases of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are still unknown. However, the association of certain etiological factors, e.g., oxidative stress, protein misfolding/aggregation, redox metal accumulation and various types of damage to the genome, to pathological changes in the affected brain region(s) have been consistently observed. While redox metal toxicity received major attention in the last decade, its potential as a therapeutic target is still at a cross-roads, mostly because of the lack of mechanistic understanding of metal dyshomeostasis in affected neurons. Furthermore, previous studies have established the role of metals in causing genome damage, both directly and via the generation of reactive oxygen species (ROS), but little was known about their impact on genome repair. Our recent studies demonstrated that excess levels of iron and copper observed in neurodegenerative disease-affected brain neurons could not only induce genome damage in neurons, but also affect their repair by oxidatively inhibiting NEIL DNA glycosylases, which initiate the repair of oxidized DNA bases. The inhibitory effect was reversed by a combination of metal chelators and reducing agents, which underscore the need for elucidating the molecular basis for the neuronal toxicity of metals in order to develop effective therapeutic approaches. In this review, we have focused on the oxidative genome damage repair pathway as a potential target for reducing pro-oxidant metal toxicity in neurological diseases. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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Open AccessReview Chaperoning Proteins for Destruction: Diverse Roles of Hsp70 Chaperones and their Co-Chaperones in Targeting Misfolded Proteins to the Proteasome
Biomolecules 2014, 4(3), 704-724; doi:10.3390/biom4030704
Received: 28 March 2014 / Revised: 31 May 2014 / Accepted: 24 June 2014 / Published: 17 July 2014
Cited by 17 | PDF Full-text (2034 KB) | HTML Full-text | XML Full-text
Abstract
Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are
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Molecular chaperones were originally discovered as heat shock-induced proteins that facilitate proper folding of proteins with non-native conformations. While the function of chaperones in protein folding has been well documented over the last four decades, more recent studies have shown that chaperones are also necessary for the clearance of terminally misfolded proteins by the Ub-proteasome system. In this capacity, chaperones protect misfolded degradation substrates from spontaneous aggregation, facilitate their recognition by the Ub ligation machinery and finally shuttle the ubiquitylated substrates to the proteasome. The physiological importance of these functions is manifested by inefficient proteasomal degradation and the accumulation of protein aggregates during ageing or in certain neurodegenerative diseases, when chaperone levels decline. In this review, we focus on the diverse roles of stress-induced chaperones in targeting misfolded proteins to the proteasome and the consequences of their compromised activity. We further discuss the implications of these findings to the identification of new therapeutic targets for the treatment of amyloid diseases. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions
Biomolecules 2014, 4(3), 725-773; doi:10.3390/biom4030725
Received: 4 February 2014 / Revised: 17 June 2014 / Accepted: 20 June 2014 / Published: 24 July 2014
Cited by 13 | PDF Full-text (5389 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last
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The discovery of Intrinsically Disordered Proteins, which contain significant levels of disorder yet perform complex biologically functions, as well as unwanted aggregation, has motivated numerous experimental and theoretical studies aimed at describing residue-level conformational ensembles. Multiple lines of evidence gathered over the last 15 years strongly suggest that amino acids residues display unique and restricted conformational preferences in the unfolded state of peptides and proteins, contrary to one of the basic assumptions of the canonical random coil model. To fully understand residue level order/disorder, however, one has to gain a quantitative, experimentally based picture of conformational distributions and to determine the physical basis underlying residue-level conformational biases. Here, we review the experimental, computational and bioinformatic evidence for conformational preferences of amino acid residues in (mostly short) peptides that can be utilized as suitable model systems for unfolded states of peptides and proteins. In this context particular attention is paid to the alleged high polyproline II preference of alanine. We discuss how these conformational propensities may be modulated by peptide solvent interactions and so called nearest-neighbor interactions. The relevance of conformational propensities for the protein folding problem and the understanding of IDPs is briefly discussed. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
Open AccessReview Emerging Mechanistic Insights into AAA Complexes Regulating Proteasomal Degradation
Biomolecules 2014, 4(3), 774-794; doi:10.3390/biom4030774
Received: 9 May 2014 / Revised: 11 June 2014 / Accepted: 21 July 2014 / Published: 6 August 2014
Cited by 3 | PDF Full-text (3463 KB) | HTML Full-text | XML Full-text
Abstract Emerging Mechanistic Insights into AAA Complexes Regulating Proteasomal Degradation Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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Open AccessReview Interactions between Calcium and Alpha-Synuclein in Neurodegeneration
Biomolecules 2014, 4(3), 795-811; doi:10.3390/biom4030795
Received: 26 March 2014 / Revised: 25 June 2014 / Accepted: 14 July 2014 / Published: 14 August 2014
Cited by 8 | PDF Full-text (18550 KB) | HTML Full-text | XML Full-text
Abstract
In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently,
[...] Read more.
In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson’s disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview The 26S Proteasome and Initiation of Gene Transcription
Biomolecules 2014, 4(3), 827-847; doi:10.3390/biom4030827
Received: 14 April 2014 / Revised: 20 August 2014 / Accepted: 1 September 2014 / Published: 10 September 2014
Cited by 5 | PDF Full-text (43928 KB) | HTML Full-text | XML Full-text
Abstract
Transcription activation is the foremost step of gene expression and is modulated by various factors that act in synergy. Misregulation of this process and its associated factors has severe effects and hence requires strong regulatory control. In recent years, growing evidence has highlighted
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Transcription activation is the foremost step of gene expression and is modulated by various factors that act in synergy. Misregulation of this process and its associated factors has severe effects and hence requires strong regulatory control. In recent years, growing evidence has highlighted the 26S proteasome as an important contributor to the regulation of transcription initiation. Well known for its role in protein destruction, its contribution to protein synthesis was initially viewed with skepticism. However, studies over the past several years have established the proteasome as an important component of transcription initiation through proteolytic and non-proteolytic activities. In this review, we discuss findings made so far in understanding the connections between transcription initiation and the 26S proteasome complex. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Particle-Rich Cytoplasmic Structure (PaCS): Identification, Natural History, Role in Cell Biology and Pathology
Biomolecules 2014, 4(3), 848-861; doi:10.3390/biom4030848
Received: 28 March 2014 / Revised: 13 August 2014 / Accepted: 5 September 2014 / Published: 22 September 2014
Cited by 1 | PDF Full-text (4648 KB) | HTML Full-text | XML Full-text
Abstract
Cytoplasmic structures showing a selective concentration of both polyubiquitinated proteins and proteasome have been described in various epithelial, hematopoietic, mesenchymal and neural cells in vitro or in fetal tissues, as well as in chronically-infected, mutated preneoplastic and neoplastic tissues. These cytoplasmic structures differ
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Cytoplasmic structures showing a selective concentration of both polyubiquitinated proteins and proteasome have been described in various epithelial, hematopoietic, mesenchymal and neural cells in vitro or in fetal tissues, as well as in chronically-infected, mutated preneoplastic and neoplastic tissues. These cytoplasmic structures differ from other ubiquitin-reactive cytoplasmic bodies, like sequestosomes, aggresome-like-induced structures in dendritic cells (DALIS)/non-dendritic cells (ALIS) and aggresomes in showing distinctive ultrastructural organization (particle-rich cytoplasmic structure or PaCS), a cytochemical pattern and a functional profile. Their formation can be induced in vitro in dendritic or natural killer cells by trophic factors and interleukin treatment. They originate in close connection with ribosomes, while, as a result of their growth, the cytoskeleton and other surrounding organelles are usually dislocated outside their core. Interestingly, these particulate cytoplasmic structures are often found to fill cytoplasmic blebs forming proteasome- and polyubiquitinated protein-discharging vesicles, called ectosomes, which are found to detach from the cell and freely float in the extracellular space. To clearly point out the importance of the polyubiquitinated proteins and proteasome containing cytoplasmic structures, their role in cell biology and pathology has been carefully analyzed. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Regulating the 20S Proteasome Ubiquitin-Independent Degradation Pathway
Biomolecules 2014, 4(3), 862-884; doi:10.3390/biom4030862
Received: 4 May 2014 / Revised: 27 August 2014 / Accepted: 5 September 2014 / Published: 23 September 2014
Cited by 23 | PDF Full-text (11581 KB) | HTML Full-text | XML Full-text
Abstract
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by the core 20S proteasome itself. Degradation by the 20S proteasome does not
[...] Read more.
For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by the core 20S proteasome itself. Degradation by the 20S proteasome does not require ubiquitin tagging or the presence of the 19S regulatory particle; rather, it relies on the inherent structural disorder of the protein being degraded. Thus, proteins that contain unstructured regions due to oxidation, mutation, or aging, as well as naturally, intrinsically unfolded proteins, are susceptible to 20S degradation. Unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome, relatively little is known about the means by which 20S-mediated proteolysis is controlled. Here, we describe our current understanding of the regulatory mechanisms that coordinate 20S proteasome-mediated degradation, and highlight the gaps in knowledge that remain to be bridged. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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