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Biomolecules, Volume 4, Issue 2 (June 2014), Pages 374-599

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Research

Jump to: Review

Open AccessArticle Isolation and Characterization of a Novel Rebaudioside M Isomer from a Bioconversion Reaction of Rebaudioside A and NMR Comparison Studies of Rebaudioside M Isolated from Stevia rebaudiana Bertoni and Stevia rebaudiana Morita
Biomolecules 2014, 4(2), 374-389; doi:10.3390/biom4020374
Received: 30 January 2014 / Revised: 12 March 2014 / Accepted: 13 March 2014 / Published: 31 March 2014
Cited by 5 | PDF Full-text (271 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A minor product, rebaudioside M2 (2), from the bioconversion reaction of rebaudioside A (4) to rebaudioside D (3), was isolated and the complete structure of the novel steviol glycoside was determined. Rebaudioside M2 (2) [...] Read more.
A minor product, rebaudioside M2 (2), from the bioconversion reaction of rebaudioside A (4) to rebaudioside D (3), was isolated and the complete structure of the novel steviol glycoside was determined. Rebaudioside M2 (2) is considered an isomer of rebaudioside M (1) and contains a relatively rare 16 sugar linkage. It was isolated and characterized with NMR (1H, 13C, COSY, HSQC-DEPT, HMBC, 1D-TOCSY, and NOESY) and mass spectral data. Additionally, we emphasize the importance of 1D and 2D NMR techniques when identifying complex steviol glycosides. Numerous NMR spectroscopy studies of rebaudioside M (1), rebaudioside D (3), and mixture of 1 and 3 led to the discovery that SG17 which was previously reported in literature, is a mixture of rebaudioside D (3), rebaudioside M (1), and possibly other related steviol glycosides. Full article
Open AccessArticle Enhanced Adsorption and Recovery of Uranyl Ions by NikR Mutant-Displaying Yeast
Biomolecules 2014, 4(2), 390-401; doi:10.3390/biom4020390
Received: 4 February 2014 / Revised: 12 March 2014 / Accepted: 14 March 2014 / Published: 11 April 2014
Cited by 3 | PDF Full-text (379 KB) | HTML Full-text | XML Full-text
Abstract
Uranium is one of the most important metal resources, and the technology for the recovery of uranyl ions (UO22+) from aqueous solutions is required to ensure a semi-permanent supply of uranium. The NikR protein is a Ni2+-dependent [...] Read more.
Uranium is one of the most important metal resources, and the technology for the recovery of uranyl ions (UO22+) from aqueous solutions is required to ensure a semi-permanent supply of uranium. The NikR protein is a Ni2+-dependent transcriptional repressor of the nickel-ion uptake system in Escherichia coli, but its mutant protein (NikRm) is able to selectively bind uranyl ions in the interface of the two monomers. In this study, NikRm protein with ability to adsorb uranyl ions was displayed on the cell surface of Saccharomyces cerevisiae. To perform the binding of metal ions in the interface of the two monomers, two metal-binding domains (MBDs) of NikRm were tandemly fused via linker peptides and displayed on the yeast cell surface by fusion with the cell wall-anchoring domain of yeast α-agglutinin. The NikRm-MBD-displaying yeast cells with particular linker lengths showed the enhanced adsorption of uranyl ions in comparison to the control strain. By treating cells with citrate buffer (pH 4.3), the uranyl ions adsorbed on the cell surface were recovered. Our results indicate that the adsorption system by yeast cells displaying tandemly fused MBDs of NikRm is effective for simple and concentrated recovery of uranyl ions, as well as adsorption of uranyl ions. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessArticle Chaperonin GroEL Reassembly: An Effect of Protein Ligands and Solvent Composition
Biomolecules 2014, 4(2), 458-473; doi:10.3390/biom4020458
Received: 10 September 2013 / Revised: 28 March 2014 / Accepted: 2 April 2014 / Published: 22 April 2014
Cited by 2 | PDF Full-text (2071 KB) | HTML Full-text | XML Full-text
Abstract
Chaperonin GroEL is a complex oligomeric heat shock protein (Hsp60) assisting the correct folding and assembly of other proteins in the cell. An intriguing question is how GroEL folds itself. According to the literature, GroEL reassembly is dependent on chaperonin ligands and [...] Read more.
Chaperonin GroEL is a complex oligomeric heat shock protein (Hsp60) assisting the correct folding and assembly of other proteins in the cell. An intriguing question is how GroEL folds itself. According to the literature, GroEL reassembly is dependent on chaperonin ligands and solvent composition. Here we demonstrate dependence of GroEL reassembly efficiency on concentrations of the essential factors (Mg2+, ADP, ATP, GroES, ammonium sulfate, NaCl and glycerol). Besides, kinetics of GroEL oligomerization in various conditions was monitored by the light scattering technique and proved to be two-exponential, which suggested accumulation of a certain oligomeric intermediate. This intermediate was resolved as a heptamer by nondenaturing blue electrophoresis of GroEL monomers during their assembly in the presence of both Mg-ATP and co-chaperonin GroES. Presumably, this intermediate heptamer plays a key role in formation of the GroEL tetradecameric particle. The role of co-chaperonin GroES (Hsp10) in GroEL assembly is also discussed. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
Open AccessArticle Prion Fragment Peptides Are Digested with Membrane Type Matrix Metalloproteinases and Acquire Enzyme Resistance through Cu2+-Binding
Biomolecules 2014, 4(2), 510-526; doi:10.3390/biom4020510
Received: 31 January 2014 / Revised: 2 April 2014 / Accepted: 11 April 2014 / Published: 8 May 2014
Cited by 2 | PDF Full-text (1518 KB) | HTML Full-text | XML Full-text
Abstract
Prions are the cause of neurodegenerative disease in humans and other mammals. The structural conversion of the prion protein (PrP) from a normal cellular protein (PrPC) to a protease-resistant isoform (PrPSc) is thought to relate to Cu2+ [...] Read more.
Prions are the cause of neurodegenerative disease in humans and other mammals. The structural conversion of the prion protein (PrP) from a normal cellular protein (PrPC) to a protease-resistant isoform (PrPSc) is thought to relate to Cu2+ binding to histidine residues. In this study, we focused on the membrane-type matrix metalloproteinases (MT-MMPs) such as MT1-MMP and MT3-MMP, which are expressed in the brain as PrPC-degrading proteases. We synthesized 21 prion fragment peptides. Each purified peptide was individually incubated with recombinant MT1-MMP or MT3-MMP in the presence or absence of Cu2+ and the cleavage sites determined by LC-ESI-MS analysis. Recombinant MMP-7 and human serum (HS) were also tested as control. hPrP61-90, from the octapeptide-repeat region, was cleaved by HS but not by the MMPs tested here. On the other hand, hPrP92-168 from the central region was cleaved by MT1-MMP and MT3-MMP at various sites. These cleavages were inhibited by treatment with Cu2+. The C-terminal peptides had higher resistance than the central region. The data obtained from this study suggest that MT-MMPs expressed in the brain might possess PrPC-degrading activity. Full article

Review

Jump to: Research

Open AccessReview Design of Catalytically Amplified Sensors for Small Molecules
Biomolecules 2014, 4(2), 402-418; doi:10.3390/biom4020402
Received: 6 February 2014 / Revised: 21 March 2014 / Accepted: 26 March 2014 / Published: 17 April 2014
Cited by 7 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Catalytically amplified sensors link an allosteric analyte binding site with a reactive site to catalytically convert substrate into colored or fluorescent product that can be easily measured. Such an arrangement greatly improves a sensor’s detection limit as illustrated by successful application of [...] Read more.
Catalytically amplified sensors link an allosteric analyte binding site with a reactive site to catalytically convert substrate into colored or fluorescent product that can be easily measured. Such an arrangement greatly improves a sensor’s detection limit as illustrated by successful application of ELISA-based approaches. The ability to engineer synthetic catalytic sites into non-enzymatic proteins expands the repertoire of analytes as well as readout reactions. Here we review recent examples of small molecule sensors based on allosterically controlled enzymes and organometallic catalysts. The focus of this paper is on biocompatible, switchable enzymes regulated by small molecules to track analytes both in vivo and in the environment. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview Zinc-Binding Cysteines: Diverse Functions and Structural Motifs
Biomolecules 2014, 4(2), 419-434; doi:10.3390/biom4020419
Received: 6 February 2014 / Revised: 19 March 2014 / Accepted: 20 March 2014 / Published: 17 April 2014
Cited by 17 | PDF Full-text (2804 KB) | HTML Full-text | XML Full-text
Abstract
Cysteine residues are known to perform essential functions within proteins, including binding to various metal ions. In particular, cysteine residues can display high affinity toward zinc ions (Zn2+), and these resulting Zn2+-cysteine complexes are critical mediators of protein [...] Read more.
Cysteine residues are known to perform essential functions within proteins, including binding to various metal ions. In particular, cysteine residues can display high affinity toward zinc ions (Zn2+), and these resulting Zn2+-cysteine complexes are critical mediators of protein structure, catalysis and regulation. Recent advances in both experimental and theoretical platforms have accelerated the identification and functional characterization of Zn2+-bound cysteines. Zn2+-cysteine complexes have been observed across diverse protein classes and are known to facilitate a variety of cellular processes. Here, we highlight the structural characteristics and diverse functional roles of Zn2+-cysteine complexes in proteins and describe structural, computational and chemical proteomic technologies that have enabled the global discovery of novel Zn2+-binding cysteines. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview Metallothioneins, Unconventional Proteins from Unconventional Animals: A Long Journey from Nematodes to Mammals
Biomolecules 2014, 4(2), 435-457; doi:10.3390/biom4020435
Received: 30 January 2014 / Revised: 19 March 2014 / Accepted: 21 March 2014 / Published: 22 April 2014
Cited by 6 | PDF Full-text (1243 KB) | HTML Full-text | XML Full-text
Abstract
Metallothioneins (MTs) are ubiquitous low molecular weight cysteine-rich proteins characterized by high affinity for d10 electron configuration metals, including essential (Zn and Cu) and non-essential (Cd and Hg) trace elements. The biological role of these ancient and well-conserved multifunctional proteins has been [...] Read more.
Metallothioneins (MTs) are ubiquitous low molecular weight cysteine-rich proteins characterized by high affinity for d10 electron configuration metals, including essential (Zn and Cu) and non-essential (Cd and Hg) trace elements. The biological role of these ancient and well-conserved multifunctional proteins has been debated since MTs were first discovered in 1957. Their main hypothesized functions are: (1) homeostasis of Zn and Cu; (2) detoxification of Cd, and Hg; and (3) free radical scavenging. This review will focus on MTs in unconventional animals, those not traditionally studied in veterinary medicine but of increasing interest in this field of research. Living in different environments, these animals represent an incredible source of physiological and biochemical adaptations still partly unexplored. The study of metal-MT interactions is of great interest for clinicians and researchers working in veterinary medicine, food quality and endangered species conservation. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview The Role of Histidine-Proline-Rich Glycoprotein as Zinc Chaperone for Skeletal Muscle AMP Deaminase
Biomolecules 2014, 4(2), 474-497; doi:10.3390/biom4020474
Received: 6 February 2014 / Revised: 8 April 2014 / Accepted: 10 April 2014 / Published: 5 May 2014
Cited by 2 | PDF Full-text (1057 KB) | HTML Full-text | XML Full-text
Abstract
Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in [...] Read more.
Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal muscle by the Zn2+ metalloenzyme AMP deaminase (AMPD) and the metal binding protein histidine-proline-rich glycoprotein (HPRG) acts in this manner. HPRG is a major plasma protein. Recent investigations have reported that skeletal muscle cells do not synthesize HPRG but instead actively internalize plasma HPRG. X-ray absorption spectroscopy (XAS) performed on fresh preparations of rabbit skeletal muscle AMPD provided evidence for a dinuclear zinc site in the enzyme compatible with a (μ-aqua)(μ-carboxylato)dizinc(II) core with two histidine residues at each metal site. XAS on HPRG isolated from the AMPD complex showed that zinc is bound to the protein in a dinuclear cluster where each Zn2+ ion is coordinated by three histidine and one heavier ligand, likely sulfur from cysteine. We describe the existence in mammalian HPRG of a specific zinc binding site distinct from the His-Pro-rich region. The participation of HPRG in the assembly and maintenance of skeletal muscle AMPD by acting as a zinc chaperone is also demonstrated. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview Decoding F508del Misfolding in Cystic Fibrosis
Biomolecules 2014, 4(2), 498-509; doi:10.3390/biom4020498
Received: 28 February 2014 / Revised: 11 April 2014 / Accepted: 25 April 2014 / Published: 6 May 2014
Cited by 2 | PDF Full-text (675 KB) | HTML Full-text | XML Full-text
Abstract
The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to [...] Read more.
The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1’s interactions with other domains. Such global misfolding produces a mutant chloride channel that is impaired in exocytic trafficking, peripheral stability, and channel gating. The nature and atomic details of F508del misfolding have been subject to extensive research during the past decade. Current data support a central role for NBD1 in F508del misfolding and rescue. Many cis-acting NBD1 second-site mutations rescue F508del misfolding in the context of full-length CFTR. While some of these mutations appear to specifically counteract the F508del-induced misfolding, others release certain inherent conformational constraints of the human wild-type CFTR. Several small-molecule correctors were recently found to act on key interdomain interfaces of F508del CFTR. Potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508del CFTR. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
Open AccessReview Structure and Function of the LmbE-like Superfamily
Biomolecules 2014, 4(2), 527-545; doi:10.3390/biom4020527
Received: 6 February 2014 / Revised: 18 April 2014 / Accepted: 18 April 2014 / Published: 16 May 2014
Cited by 1 | PDF Full-text (2377 KB) | HTML Full-text | XML Full-text
Abstract
The LmbE-like superfamily is comprised of a series of enzymes that use a single catalytic metal ion to catalyze the hydrolysis of various substrates. These substrates are often key metabolites for eukaryotes and prokaryotes, which makes the LmbE-like enzymes important targets for [...] Read more.
The LmbE-like superfamily is comprised of a series of enzymes that use a single catalytic metal ion to catalyze the hydrolysis of various substrates. These substrates are often key metabolites for eukaryotes and prokaryotes, which makes the LmbE-like enzymes important targets for drug development. Herein we review the structure and function of the LmbE-like proteins identified to date. While this is the newest superfamily of metallohydrolases, a growing number of functionally interesting proteins from this superfamily have been characterized. Available crystal structures of LmbE-like proteins reveal a Rossmann fold similar to lactate dehydrogenase, which represented a novel fold for (zinc) metallohydrolases at the time the initial structure was solved. The structural diversity of the N-acetylglucosamine containing substrates affords functional diversity for the LmbE-like enzyme superfamily. The majority of enzymes identified to date are metal-dependent deacetylases that catalyze the hydrolysis of a N-acetylglucosamine moiety on substrate using a combination of amino acid side chains and a single bound metal ion, predominantly zinc. The catalytic zinc is coordinated to proteins via His2-Asp-solvent binding site. Additionally, studies indicate that protein dynamics play important roles in regulating access to the active site and facilitating catalysis for at least two members of this protein superfamily. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview Evolutionary Implications of Metal Binding Features in Different Species’ Prion Protein: An Inorganic Point of View
Biomolecules 2014, 4(2), 546-565; doi:10.3390/biom4020546
Received: 20 February 2014 / Revised: 29 April 2014 / Accepted: 6 May 2014 / Published: 23 May 2014
Cited by 2 | PDF Full-text (436 KB) | HTML Full-text | XML Full-text
Abstract
Prion disorders are a group of fatal neurodegenerative conditions of mammals. The key molecular event in the pathogenesis of such diseases is the conformational conversion of prion protein, PrPC, into a misfolded form rich in β-sheet structure, PrPSc, [...] Read more.
Prion disorders are a group of fatal neurodegenerative conditions of mammals. The key molecular event in the pathogenesis of such diseases is the conformational conversion of prion protein, PrPC, into a misfolded form rich in β-sheet structure, PrPSc, but the detailed mechanistic aspects of prion protein conversion remain enigmatic. There is uncertainty on the precise physiological function of PrPC in healthy individuals. Several evidences support the notion of its role in copper homeostasis. PrPC binds Cu2+ mainly through a domain composed by four to five repeats of eight amino acids. In addition to mammals, PrP homologues have also been identified in birds, reptiles, amphibians and fish. The globular domain of protein is retained in the different species, suggesting that the protein carries out an essential common function. However, the comparison of amino acid sequences indicates that prion protein has evolved differently in each vertebrate class. The primary sequences are strongly conserved in each group, but these exhibit a low similarity with those of mammals. The N-terminal domain of different prions shows tandem amino acid repeats with an increasing amount of histidine residues going from amphibians to mammals. The difference in the sequence affects the number of copper binding sites, the affinity and the coordination environment of metal ions, suggesting that the involvement of prion in metal homeostasis may be a specific characteristic of mammalian prion protein. In this review, we describe the similarities and the differences in the metal binding of different species’ prion protein, as revealed by studies carried out on the entire protein and related peptide fragments. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
Open AccessReview PA28αβ: The Enigmatic Magic Ring of the Proteasome?
Biomolecules 2014, 4(2), 566-584; doi:10.3390/biom4020566
Received: 4 April 2014 / Revised: 15 May 2014 / Accepted: 8 June 2014 / Published: 19 June 2014
Cited by 10 | PDF Full-text (145 KB) | HTML Full-text | XML Full-text
Abstract
PA28αβ is a γ-interferon-induced 11S complex that associates with the ends of the 20S proteasome and stimulates in vitro breakdown of small peptide substrates, but not proteins or ubiquitin-conjugated proteins. In cells, PA28 also exists in larger complexes along with the 19S [...] Read more.
PA28αβ is a γ-interferon-induced 11S complex that associates with the ends of the 20S proteasome and stimulates in vitro breakdown of small peptide substrates, but not proteins or ubiquitin-conjugated proteins. In cells, PA28 also exists in larger complexes along with the 19S particle, which allows ATP-dependent degradation of proteins; although in vivo a large fraction of PA28 is present as PA28αβ-20S particles whose exact biological functions are largely unknown. Although several lines of evidence strongly indicate that PA28αβ plays a role in MHC class I antigen presentation, the exact molecular mechanisms of this activity are still poorly understood. Herein, we review current knowledge about the biochemical and biological properties of PA28αβ and discuss recent findings concerning its role in modifying the spectrum of proteasome’s peptide products, which are important to better understand the molecular mechanisms and biological consequences of PA28αβ activity. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)
Open AccessReview Modelling Proteasome and Proteasome Regulator Activities
Biomolecules 2014, 4(2), 585-599; doi:10.3390/biom4020585
Received: 25 March 2014 / Revised: 28 May 2014 / Accepted: 30 May 2014 / Published: 20 June 2014
Cited by 1 | PDF Full-text (335 KB) | HTML Full-text | XML Full-text
Abstract
Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded [...] Read more.
Proteasomes are key proteases involved in a variety of processes ranging from the clearance of damaged proteins to the presentation of antigens to CD8+ T-lymphocytes. Which cleavage sites are used within the target proteins and how fast these proteins are degraded have a profound impact on immune system function and many cellular metabolic processes. The regulation of proteasome activity involves different mechanisms, such as the substitution of the catalytic subunits, the binding of regulatory complexes to proteasome gates and the proteasome conformational modifications triggered by the target protein itself. Mathematical models are invaluable in the analysis; and potentially allow us to predict the complex interactions of proteasome regulatory mechanisms and the final outcomes of the protein degradation rate and MHC class I epitope generation. The pioneering attempts that have been made to mathematically model proteasome activity, cleavage preference variation and their modification by one of the regulatory mechanisms are reviewed here. Full article
(This article belongs to the Special Issue Proteasomes and Its Regulators)

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