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probing the force generation and stepping behavior of cytoplasmic dynein.cytoplasmic dynein, which is the largest and arguably the most complex cytoskeletal motor protein, plays fundamental roles during cell division, nuclear positioning, and organelle and mrna transport, by generating force and movement toward the minus ends of microtubules. consequently, dynein is central to many physiological processes, and its dysfunction is implicated in human diseases. however, the molecular mechanism by which dynein produces force and movement remains poorly understood. here, ...201121909883
new insights into the ca2+-atpases that contribute to cadmium tolerance in yeast.cadmium (cd(2+)) is a toxic heavy metal which triggers several toxic effects in eukaryotes, including neurotoxicity and impaired calcium metabolism. in the model organism saccharomyces cerevisiae, the best characterized pathway for cd(2+) detoxification involves conjugation with glutathione (gsh) and subsequent transport to vacuoles by ycf1p, an atpase homologous to human mrp1 (multidrug resistance associated protein 1). however, cd(2+) tolerance also can be mediated by pmr1p, a ca(2+) pump loca ...201121911041
The genome maintenance factor Mgs1 is targeted to sites of replication stress by ubiquitylated PCNA.Mgs1, the budding yeast homolog of mammalian Werner helicase-interacting protein 1 (WRNIP1/WHIP), contributes to genome stability during undisturbed replication and in response to DNA damage. A ubiquitin-binding zinc finger (UBZ) domain directs human WRNIP1 to nuclear foci, but the functional significance of its presence and the relevant ubiquitylation targets that this domain recognizes have remained unknown. Here, we provide a mechanistic basis for the ubiquitin-binding properties of the prote ...201221911365
A single zinc finger optimizes the DNA interactions of the nucleocapsid protein of the yeast retrotransposon Ty3.Reverse transcription in retroviruses and retrotransposons requires nucleic acid chaperones, which drive the rearrangement of nucleic acid conformation. The nucleic acid chaperone properties of the human immunodeficiency virus type-1 (HIV-1) nucleocapsid (NC) protein have been extensively studied, and nucleic acid aggregation, duplex destabilization and rapid binding kinetics have been identified as major components of its activity. However, the properties of other nucleic acid chaperone protein ...201121917850
human cytomegalovirus primase ul70 specifically interacts with cellular factor snapin.genomic dna synthesis is a universally conserved process for all herpesviruses, including human cytomegalovirus (hcmv). hcmv ul70 is believed to encode the primase of the dna replication machinery, a function which requires localization in the nucleus, the site of viral dna synthesis. no host factors that interact with ul70 have been reported. in this study, we provide the first direct evidence that ul70 specifically interacts with snapin, a human protein that is predominantly localized in the c ...201121917956
The antifungal mechanism of action of zinc pyrithione.Zinc pyrithione (ZPT) is the active ingredient most commonly used in many antidandruff treatments. Despite decades of successful use to treat human scalps, little is understood about the antifungal mechanism of action of ZPT.201121919897
glutamine analogs promote cytoophidium assembly in human and drosophila cells.ctp synthase is compartmentalized within a subcellular structure, termed the cytoophidium, in a range of organisms including bacteria, yeast, fruit fly and rat. here we show that ctp synthase is also compartmentalized into cytoophidia in human cells. surprisingly, the occurrence of cytoophidia in human cells increases upon treatment with a glutamine analog 6-diazo-5-oxo-l-norleucine (don), an inhibitor of glutamine-dependent enzymes including ctp synthase. experiments in flies confirmed that don ...201121930098
mutations in the dimer interface of dihydrolipoamide dehydrogenase promote site-specific oxidative damages in yeast and human cells.dihydrolipoamide dehydrogenase (dld) is a multifunctional protein well characterized as the e3 component of the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes. previously, conditions predicted to destabilize the dld dimer revealed that dld could also function as a diaphorase and serine protease. however, the relevance of these cryptic activities remained undefined. we analyzed human dld mutations linked to strikingly different clinical phenotypes, including e340k, d444v, r447 ...201121930696
Replication protein A (RPA) hampers the processive action of APOBEC3G cytosine deaminase on single-stranded DNA.BACKGROUND: Editing deaminases have a pivotal role in cellular physiology. A notable member of this superfamily, APOBEC3G (A3G), restricts retroviruses, and Activation Induced Deaminase (AID) generates antibody diversity by localized deamination of cytosines in DNA. Unconstrained deaminase activity can cause genome-wide mutagenesis and cancer. The mechanisms that protect the genomic DNA from the undesired action of deaminases are unknown. Using the in vitro deamination assays and expression of A ...201121935481
aggresome formation and segregation of inclusions influence toxicity of α-synuclein and synphilin-1 in yeast.pd (parkinson's disease) is a neurodegenerative disorder, caused by a selective loss of dopaminergic neurons in the substantia nigra, which affects an increasing number of the elderly population worldwide. one of the major hallmarks of pd is the occurrence of intracellular protein deposits in the dying neurons, termed lewy bodies, which contain different proteins, including aggregated α-synuclein and its interacting protein synphilin-1. during the last decade, a number of groups developed yeast ...201121936837
wdr36 acts as a scaffold protein tethering a g-protein-coupled receptor, gαq and phospholipase cβ in a signalling complex.we identified the wd-repeat-containing protein, wdr36, as an interacting partner of the β isoform of thromboxane a(2) receptor (tpβ) by yeast two-hybrid screening. we demonstrated that wdr36 directly interacts with the c-terminus and the first intracellular loop of tpβ by in vitro gst-pulldown assays. the interaction in a cellular context was observed by co-immunoprecipitation, which was positively affected by tpβ stimulation. tpβ-wdr36 colocalization was detected by confocal microscopy at the p ...201121940795
isoleucyl-trna synthetase levels modulate the penetrance of a homoplasmic m.4277t>c mitochondrial trna(ile) mutation causing hypertrophic cardiomyopathy.the genetic and epigenetic factors underlying the variable penetrance of homoplasmic mitochondrial dna mutations are poorly understood. we investigated a 16-year-old patient with hypertrophic cardiomyopathy harboring a homoplasmic m.4277t>c mutation in the mt-trna(ile) (mtti) gene. skeletal muscle showed multiple respiratory chain enzyme abnormalities and a decreased steady-state level of the mutated mt-trna(ile). transmitochondrial cybrids grown on galactose medium demonstrated a functional eff ...201221945886
human yeast-specific cd8 t lymphocytes show a nonclassical effector molecule profile.pathogenic yeast and fungi represent a major group of human pathogens. the consequences of infections are diverse and range from local, clinically uncomplicated mycosis of the skin to systemic, life-threatening sepsis. despite extensive mhc class i-restricted frequencies of yeast-specific cd8 t lymphocytes in healthy individuals and the essential role of the cell-mediated immunity in controlling infections, the characteristics and defense mechanisms of antifungal effector cells are still unclear ...201121947167
ubiquitin ligase nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway.α-synuclein is an abundant brain protein that binds to lipid membranes and is involved in the recycling of presynaptic vesicles. in parkinson disease, α-synuclein accumulates in intraneuronal inclusions often containing ubiquitin chains. here we show that the ubiquitin ligase nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates α-synuclein, unlike ligases previously implicated in its degradation. purified nedd4 recognizes the carboxyl terminus of α-synuclein (residue ...201121953697
The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking.Dopaminergic signaling and plasticity are essential to numerous CNS functions and pathologies, including movement, cognition, and addiction. The amphetamine- and cocaine-sensitive dopamine (DA) transporter (DAT) tightly controls extracellular DA concentrations and half-life. DAT function and surface expression are not static but are dynamically modulated by membrane trafficking. We recently demonstrated that the DAT C terminus encodes a PKC-sensitive internalization signal that also suppresses b ...201121957239
ms3 eliminates ratio distortion in isobaric multiplexed quantitative proteomics.quantitative mass spectrometry-based proteomics is highly versatile but not easily multiplexed. isobaric labeling strategies allow mass spectrometry-based multiplexed proteome quantification; however, ratio distortion owing to protein quantification interference is a common effect. we present a two-proteome model (mixture of human and yeast proteins) in a sixplex isobaric labeling system to fully document the interference effect, and we report that applying triple-stage mass spectrometry (ms3) a ...201121963607
actinomyces naturae sp. nov., the first actinomyces sp. isolated from a non-human or animal source.three facultatively anaerobic, gram-positive staining, rod-shaped, non-spore forming, flagellated bacterial strains, bl-75, bl-79(t) and bl-104, were isolated from chlorinated solvent-contaminated groundwater. phylogenetic analysis based on 16s rrna gene sequence comparisons showed them to represent a distinct lineage within the genus actinomyces with sequence identities in the range of <88-95.4% with previously described actinomyces species. the strains were oxidase and catalase negative. nitra ...201221965039
hepatic sirt1 deficiency in mice impairs mtorc2/akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance.insulin resistance is a major risk factor for type 2 diabetes mellitus. the protein encoded by the sirtuin 1 (sirt1) gene, which is a mouse homolog of yeast sir2, is implicated in the regulation of glucose metabolism and insulin sensitivity; however, the underlying mechanism remains elusive. here, using mice with a liver-specific null mutation of sirt1, we have identified a signaling pathway involving sirt1, rictor (a component of mtor complex 2 [mtorc2]), akt, and foxo1 that regulates gluconeog ...201121965330
A role for SUMO in nucleotide excision repair.The two Siz/PIAS SUMO E3 ligases Siz1 and Siz2 are responsible for the vast majority of sumoylation in Saccharomyces cerevisiae. We found that siz1? siz2? mutants are sensitive to ultra-violet (UV) light. Epistasis analysis showed that the SIZ genes act in the nucleotide excision repair (NER) pathway, and suggested that they participate both in global genome repair (GGR) and in the Rpb9-dependent subpathway of transcription-coupled repair (TCR), but have minimal role in Rad26-dependent TCR. Quan ...201121968059
endoplasmic reticulum-associated degradation (erad) and free oligosaccharide generation in saccharomyces cerevisiae.in saccharomyces cerevisiae, proteins with misfolded lumenal, membrane, and cytoplasmic domains are cleared from the endoplasmic reticulum (er) by er-associated degradation (erad)-l, -m, and -c, respectively. erad-l is n-glycan-dependent and is characterized by er mannosidase (mns1p) and er mannosidase-like protein (mnl1p), which generate man(7)glcnac(2) (d1) n-glycans with non-reducing α1,6-mannosyl residues. glycoproteins bearing this motif bind yos9p and are dislocated into the cytoplasm and ...201121979948
options for the production of selenized chicken meat.a 42-day experiment was conducted to compare the effects of various levels of sodium selenite (ss) and se-enriched yeast (sy) on chicken productivity, carcass traits, and breast se concentration. six hundred 1-day-old cobb 500 broiler chicks were placed on 1 of 6 experimental treatments. the treatments consisted of feeding a diet without se supplementation (basal diet) or basal diet with 0.6 mg/kg supplemented se supplied by ss, sy, or a mix of the two (0.45 ss + 0.15 sy; 0.3 ss + 0.3 sy; 0.15 s ...201121986861
species of candida isolated from anatomically distinct sites in military personnel in cuiabá, mato grosso, brazil.some fungi are natural inhabitants of the human body but may result in disease when conditions are conducive to their development. yeast infections are common and often occur in the skin and mucous membranes; however emerging species have changed this epidemiological profile. the ability to colonize different anatomical sites has been associated with the pathogenicity of candida when environmental conditions are particularly favorable. in the case of hot, humid climates, the attrition suffered b ...201121987132
toward an understanding of the protein interaction network of the human liver.proteome-scale protein interaction maps are available for many organisms, ranging from bacteria, yeast, worms and flies to humans. these maps provide substantial new insights into systems biology, disease research and drug discovery. however, only a small fraction of the total number of human protein-protein interactions has been identified. in this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human ...201121988832
comparison of humoral immune responses to epstein-barr virus and kaposi's sarcoma-associated herpesvirus using a viral proteome microarray.epstein-barr virus (ebv) is a ubiquitous herpesvirus, and kaposi's sarcoma-associated herpesvirus (kshv) has a restricted seroprevalence. both viruses are associated with malignancies that have an increased frequency in individuals who are coinfected with human immunodeficiency virus type 1 (hiv-1).201121990424
ATM controls meiotic double-strand-break formation.In many organisms, developmentally programmed double-strand breaks (DSBs) formed by the SPO11 transesterase initiate meiotic recombination, which promotes pairing and segregation of homologous chromosomes. Because every chromosome must receive a minimum number of DSBs, attention has focused on factors that support DSB formation. However, improperly repaired DSBs can cause meiotic arrest or mutation; thus, having too many DSBs is probably as deleterious as having too few. Only a small fraction of ...201122002603
a new high resolution screening method for study of phenotype stress responses of saccharomyces cerevisae mutants.a high resolution high throughput screening method has been developed for stress response phenotyping of the global saccharomyces cerevisiae knock out mutant collection. stress causing agent is added at three concentrations to individual mutant cultures growing in early exponentially phase in 384-well microplates, and the dynamic effect of stress agent exposure is measured by following subsequent growth profiles of individual mutants with a resolution of three optical density measurements per ho ...201122008504
the tpr-containing domain within est1 homologs exhibits species-specific roles in telomerase interaction and telomere length homeostasis.the first telomerase-associated protein (est1) was isolated in yeast due to its essential role in telomere maintenance. the human counterparts est1a, est1b, and est1c perform diverse functions in nonsense-mediated mrna decay (nmd), telomere length homeostasis, and telomere transcription. although est1 and est1a/b interact with the catalytic subunit of yeast and human telomerase (est2 and tert, respectively), the molecular determinants of these interactions have not been elaborated fully.201122011238
recql5 cooperates with topoisomerase ii alpha in dna decatenation and cell cycle progression.dna decatenation mediated by topoisomerase ii is required to separate the interlinked sister chromatids post-replication. sgs1, a yeast homolog of the human recq family of helicases interacts with topoisomerase ii and plays a role in chromosome segregation, but this functional interaction has yet to be identified in higher organisms. here, we report a physical and functional interaction of topoisomerase iiα with recql5, one of five mammalian recq helicases, during dna replication. direct interac ...201122013166
flavivirus ns3 and ns5 proteins interaction network: a high-throughput yeast two-hybrid screen.the genus flavivirus encompasses more than 50 distinct species of arthropod-borne viruses, including several major human pathogens, such as west nile virus, yellow fever virus, japanese encephalitis virus and the four serotypes of dengue viruses (denv type 1-4). each year, flaviviruses cause more than 100 million infections worldwide, some of which lead to life-threatening conditions such as encephalitis or haemorrhagic fever. among the viral proteins, ns3 and ns5 proteins constitute the major e ...201122014111
myst protein acetyltransferase activity requires active site lysine autoacetylation.the myst protein lysine acetyltransferases are evolutionarily conserved throughout eukaryotes and acetylate proteins to regulate diverse biological processes including gene regulation, dna repair, cell-cycle regulation, stem cell homeostasis and development. here, we demonstrate that myst protein acetyltransferase activity requires active site lysine autoacetylation. the x-ray crystal structures of yeast esa1 (yesa1/kat5) bound to a bisubstrate h4k16coa inhibitor and human mof (hmof/kat8/myst1) ...201122020126
Rad51 paralogues Rad55-Rad57 balance the antirecombinase Srs2 in Rad51 filament formation.Homologous recombination is a high-fidelity DNA repair pathway. Besides a critical role in accurate chromosome segregation during meiosis, recombination functions in DNA repair and in the recovery of stalled or broken replication forks to ensure genomic stability. In contrast, inappropriate recombination contributes to genomic instability, leading to loss of heterozygosity, chromosome rearrangements and cell death. The RecA/UvsX/RadA/Rad51 family of proteins catalyses the signature reactions of ...201122020281
Cell-penetrating peptides as antifungals towards Malassezia sympodialis.Aim: To determine whether different antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) are able to inhibit the growth of the commensal yeast Malassezia sympodialis, which can act as a trigger factor in different skin disorders, such as atopic eczema (AE), seborrhoeic eczema (SE) and dandruff. Methods and results: The antifungal activity of 21 different AMPs and CPPs was investigated by microdilution assay and plate counting to determine the number of colony forming units. Five ...201222023266
proteome-wide detection of abl1 sh3 binding peptides by integrating computational prediction and peptide microarray.protein-protein interactions are essential for regulating almost all aspects of cellular functions. many of these interactions are mediated by weak and transient protein domain-peptide binding, but they are often underrepresented in high throughput screening of protein-protein interactions using techniques such as yeast two hybrid and mass spectrometry. on the other hand, computational predictions and in vitro binding assays are valuable in providing clues of in vivo interactions. we present her ...201122023807
Functional links between Aß toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast.Aß (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aß toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aß was previously unknown. The factors identified in yeast modified Aß toxicity in glutamatergic neurons of Caenorhabditis elega ...201122033521
bnrch gene inhibits cell growth of hela cells through increasing the g2 phase of cell cycle.the ubiquitin-proteasome pathway (upp) is an important protein degradation system universally existing in eukaryotic organisms from yeast to human. in this system, hundreds of e3 ubiquitin-protein ligases are most important because they provide the substrate specificity and control many cellular processes. upp has been found to be relevant to cancer development. bnrch, the protein product from a novel gene isolated from brassica napus, also has e3 ubiquitin-protein ligase activity. in order to e ...201122038067
fhl2 protein is a novel co-repressor of nuclear receptor nur77.the three members of the nr4a orphan nuclear receptor subfamily nur77, nurr1, and nor-1, regulate a variety of biological functions including vascular disease and metabolism. in this study, we identified four and a half lim domains protein-2 (fhl2) as a novel interacting protein of nr4a nuclear receptors by yeast two-hybrid screen and co-immunoprecipitation studies. each of the four lim domains of fhl2 can bind nur77, and both the amino-terminal domain and the dna binding domain of nur77 are inv ...201122049082
insights into noncanonical e1 enzyme activation from the structure of autophagic e1 atg7 with atg8.autophagy is the degradation of cellular organelles via the lysosomal pathway. the autophagic ubiquitin-like (ubl) molecule atg8 is activated by the e1-like enzyme atg7. as this noncanonical e1 enzyme's domain organization is unique among ubl-activating e1 enzymes, the structural basis for its interactions with atg8 and partner e2 enzymes remains obscure. here we present the structure of the n-terminal domain of atg7, revealing a unique protein fold and interactions with both autophagic e2 enzym ...201122056771
the two-component histidine kinases drka and slna are required for in vivo growth in the human pathogen penicillium marneffei.in order to cause disease fungal pathogens must be capable of evading or tolerating the host immune defence system. one commonly utilized evasion mechanism is the ability to continually reside within macrophages of the innate immune system and survive subsequent phagocytic destruction. for intracellular growth to occur, fungal pathogens which typically grow in a filamentous hyphal form in the environment must be able to switch growth to a unicellular yeast growth form in a process known as dimor ...201122059885
Feature Article: From the Cover: A yeast functional screen predicts new candidate ALS disease genes.Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates ...201122065782
cpth6, a thiazole derivative, induces histone hypoacetylation and apoptosis in human leukemia cells.purpose: we previously identified novel thiazole derivatives able to reduce histone acetylation and histone acetyltransferase (hat) activity in yeast. among these compounds, 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (cpth6) has been selected and used throughout this study. experimental design: the effect of cpth6 on histone acetylation, cell viability and differentiation, cell-cycle distribution, and apoptosis in a panel of acute myeloid leukemia and solid tumor cell ...201122068659
split-protein systems: beyond binary protein-protein interactions.it has been estimated that 650,000 protein-protein interactions exist in the human interactome (stumpf et al., 2008), a subset of all possible macromolecular partnerships that dictate life. thus there is a continued need for the development of sensitive and user-friendly methods for cataloguing biomacromolecules in complex environments and for detecting their interactions, modifications, and cellular location. such methods also allow for establishing differences in the interactome between a norm ...201122070901
Ex Vivo and In Vivo Inhibition of Human Rhinovirus Replication by a New Pseudosubstrate of Viral 2A Protease.Human rhinoviruses (HRVs) remain a significant public health problem as they are the major cause of both upper and lower respiratory tract infections. Unfortunately, to date no vaccine or antiviral against these pathogens is available. Here, using a high-throughput yeast two-hybrid screening, we identified a 6-amino-acid hit peptide, LVLQTM, which acted as a pseudosubstrate of the viral 2A cysteine protease (2A(pro)) and inhibited its activity. This peptide was chemically modified with a reactiv ...201222072773
mechanism of start site selection by rna polymerase ii: interplay between tfiib and ssl2/xpb helicase subunit of tfiih.tfiib is essential for transcription initiation by rna polymerase ii. tfiib also cross-links to terminator regions and is required for gene loops that juxtapose promoter-terminator elements in a transcription-dependent manner. the saccharomyces cerevisiae sua7-1 mutation encodes an altered form of tfiib (e62k) that is defective for both start site selection and gene looping. here we report the isolation of an ssl2 mutant, encoding an altered form of tfiih, as a suppressor of the cold-sensitive g ...201222081613
cuedc2 (cue domain-containing 2) and socs3 (suppressors of cytokine signaling 3) cooperate to negatively regulate janus kinase 1/signal transducers and activators of transcription 3 signaling.janus kinase 1/signal transducers and activators of transcription 3 (jak1/stat3) pathway is one of the recognized oncogenic signaling pathways that frequently overactivated in a variety of human tumors. despite rapid progress in elucidating the molecular mechanisms of activation of jak/stat pathway, the processes that regulate jak/stat deactivation need to be further clarified. here we demonstrate that cue domain-containing 2 (cuedc2) inhibits cytokine-induced phosphorylation of jak1 and stat3 a ...201222084247
MIF from mussel: Coding sequence, phylogeny, polymorphism, 3D model and regulation of expression.Three macrophage migration inhibitory factor (MIF)-related sequences were identified from a Mytilus galloprovincialis EST library. The consensus sequence included a 5'-UTR of 32 nucleotides, the complete ORF of 345 nucleotides, and a 3'-UTR of 349 nucleotides. As for other MIFs, M. galloprovincialis ORF does not include any signal or C-terminus extensions. The translated sequence of 115 amino acids possesses a molecular mass of 12,681.4, a pI of 6.27 and a stability index of 21.48. Its 3D struct ...201122085783
A Monod-Wyman-Changeux Mechanism Can Explain G Protein-coupled Receptor (GPCR) Allosteric Modulation.The Monod-Wyman-Changeux (MWC) model was initially proposed to describe the allosteric properties of regulatory enzymes and subsequently extended to receptors. Yet despite GPCRs representing the largest family of receptors and drug targets, no study has systematically evaluated the MWC mechanism as it applies to GPCR allosteric ligands. We reveal how the recently described allosteric modulator, benzyl quinolone carboxylic acid (BQCA), behaves according to a strict, two-state MWC mechanism at the ...201222086918
Candida albicans yeast and hyphae are discriminated by MAPK signaling in vaginal epithelial cells.We previously reported that a bi-phasic innate immune MAPK response, constituting activation of the mitogen-activated protein kinase (MAPK) phosphatase MKP1 and c-Fos transcription factor, discriminates between the yeast and hyphal forms of Candida albicans in oral epithelial cells (ECs). Since the vast majority of mucosal Candida infections are vaginal, we sought to determine whether a similar bi-phasic MAPK-based immune response was activated by C. albicans in vaginal ECs. Here, we demonstrate ...201122087232
elevated levels of renal and circulating nop-7-associated 2 (nsa2) in rat and mouse models of diabetes, in mesangial cells in vitro and in patients with diabetic nephropathy.aims/hypothesis: we previously found that nop-7-associated 2 (nsa2), which is involved in ribosomal biogenesis in yeast and is a putative cell cycle regulator in mammalian cells, is elevated in the kidney of goto-kakizaki (gk) rat, a spontaneous model of type 2 diabetes. here we tested the hypothesis that elevated nsa2 is involved in diabetic nephropathy (dn). methods: we examined nsa2/nsa2 expression and nsa2 pr ...201122095236
structural and binding studies of the c-terminal domains of yeast tfiif subunits tfg1 and tfg2.the general transcription factor tfiif plays essential roles at several steps during eukaryotic transcription. while several studies have offered insights into the structure/function relationship in human tfiif, much less is known about the yeast system. here, we describe the first nmr structural and binding studies of the c-terminal domains (ctds) of tfg1 and tfg2 subunits of saccharomyces cerevisiae tfiif. we used the program cs-rosetta to determine the three-dimensional folds of these domains ...201122095626
Biochemical characterization of Warsaw Breakage Syndrome helicase.Mutations in the human ChlR1 gene are associated with a unique genetic disorder known as Warsaw Breakage Syndrome characterized by cellular defects in sister chromatid cohesion and hypersensitivity to agents that induce replication stress. A role of ChlR1 helicase in sister chromatid cohesion was first evidenced by studies of the yeast homolog Chl1p; however, its cellular functions in DNA metabolism are not well understood. We have carefully examined the DNA substrate specificity of purified r ...201122102414
a non-motor microtubule binding site is essential for the high processivity and mitotic function of kinesin-8 kif18a.members of the kinesin-8 subfamily are plus end-directed molecular motors that accumulate at the plus-ends of kinetochore-microtubules (kt-mts) where they regulate mt dynamics. loss of vertebrate kinesin-8 function induces hyperstable mts and elongated mitotic spindles accompanied by severe chromosome congression defects. it has been reported that the motility of human kinesin-8, kif18a, is required for its accumulation at the plus tips of kt-mts.201122102900
oxidative protein folding: selective pressure for prolamin evolution in rice.during seed development, endosperm cells of highly productive cereals, including rice, synthesize disulfide-rich proteins in large amounts and deposit them into storage organelles. disulfide bond formation involves electron transfer and generates h 2o 2 as a by-product. to ensure proper development and maturation of seeds, the endosperm cells must supply large amounts of oxidizing equivalents to dithiols in nascent proteins in a controlled manner. this review compares multiple oxidative protein ...201122112460
Degradation of phytate by Pichia kudriavzevii TY13 and Hanseniaspora guilliermondii TY14 in Tanzanian togwa.The fermented cereal-based gruel togwa is used as weaning food for children in Tanzania. Togwa is rich in minerals but these are often not available for uptake in the human intestine due to natural inhibitors, such as phytate (IP(6)). The yeasts Pichia kudriavzevii TY13, Hanseniaspora guilliermondii TY14 and TY20, isolated from Tanzanian togwa, and selected for high phytase activity in complex yeast medium YPD, were now studied regarding their ability to degrade IP(6) in maize-based model togwa. ...201122112916
emergence of candida spp. and exploration of natural bioactive molecules for anticandidal therapy -status quo.the opportunistic yeast pathogen candida albicans and the emerging non-albicans candida spp. cause life-threatening infections in immuno-compromised patients, leading to an increase in mortality rate. at present, the emergence of non-albicans candida spp. causes serious infections that are difficult to treat the human populations worldwide. the available, synthetic antifungal drugs show high toxicity to host tissues causing adverse effects. many metabolites of terrestrial and marine plants, micr ...201122118661
non-coding telomeric and subtelomeric transcripts are differentially regulated by telomeric and heterochromatin assembly factors in fission yeast.while telomere repeat-containing non-coding rna has been identified in a variety of eukaryotes, its biological role is not yet clear. we have identified telomeric transcripts in fission yeast, a model system that combines precise genetic manipulability with telomeres remarkably similar to those of human. like human and budding yeast, fission yeast harbours a population of telomeric rna molecules containing g-rich telomeric repeats transcribed from the subtelomere to the telomere. in addition, we ...201122139922
inhibition of homologous recombination by the pcna-interacting protein pari.inappropriate homologous recombination (hr) causes genomic instability and cancer. in yeast, the uvrd family helicase srs2 is recruited to sites of dna replication by sumo-modified pcna, where it acts to restrict hr by disassembling toxic rad51 nucleofilaments. how human cells control recombination at replication forks is unknown. here, we report that the protein pari, containing a uvrd-like helicase domain, is a pcna-interacting partner required for preservation of genome stability in human and ...201122153967
Chronological lifespan in stationary culture: from yeast to human cells.Comment on: Leontieva OV and Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging 2011; 3: this issue. This first paper defines the field, providing description of the phenomenon, its mechanism and the ways of pharmacological manipulation. It illuminates the place of yeast CS in aging research and its indirect (via common signaling pathways) relevance to cancer and organismal aging. It also rules out altruistic (pro ...201122156408
recombinant antibodies and their use in biosensors.inexpensive, noninvasive immunoassays can be used to quickly detect disease in humans. immunoassay sensitivity and specificity are decidedly dependent upon high-affinity, antigen-specific antibodies. antibodies are produced biologically. as such, antibody quality and suitability for use in immunoassays cannot be readily determined or controlled by human intervention. however, the process through which high-quality antibodies can be obtained has been shortened and streamlined by use of genetic en ...201122159424
Expression of Multisubunit Proteins in Leishmania tarentolae.Heterologous gene expression in mammalian cells is the first choice for the production of recombinant proteins when posttranslational modifications affect the biological activity of target proteins. However, the expression efficiency of mammalian cells is relatively low compared to other expression systems, such as Escherichia coli or yeast. Recently, a novel protein expression system based on Leishmania tarentolae, a protozoan parasite of gecko, was developed. This system allows not only easy h ...201222160906
the global transcriptional response of fission yeast to hydrogen sulfide.hydrogen sulfide (h(2)s) is a newly identified member of the small family of gasotransmitters that are endogenous gaseous signaling molecules that have a fundamental role in human biology and disease. although it is a relatively recent discovery and the mechanism of h(2)s activity is not completely understood, it is known to be involved in a number of cellular processes; h(2)s can affect ion channels, transcription factors and protein kinases in mammals.201122164259
promiscuous domains: facilitating stability of the yeast protein-protein interaction network.domain-domain interactions are a critical type of the mechanisms mediating protein-protein interactions (ppis). for a given protein domain, its ability to combine with distinct domains is usually referred to as promiscuity or versatility. interestingly, a previous study has reported that a domain's promiscuity may reflect its ability to interact with other domains in human proteins. in this work, promiscuous domains were first identified from the yeast genome. then, we sought to determine what r ...201122166987
Fulminant Candidemia Diagnosed by Prompt Detection of Pseudohyphae in a Peripheral Blood Smear.A 77-year-old man treated with prednisolone for pemphigus developed severe sepsis by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Several antibiotics were administered. A peripheral blood smear showed growth of a large number of yeast extending pseudohyphae which could be seen both inside and outside of leucocytes. Antifungal agents were added immediately; however, he did not recover. Several days later, blood culture showed Candida albicans septicemia. The autopsy rev ...201122173051
reduced protein stability of human dj-1/park7 l166p, linked to autosomal recessive parkinson disease, is due to direct endoproteolytic cleavage by the proteasome.parkinson's disease (pd) is characterized by dopaminergic dysfunction and degeneration. dj-1/park7 mutations have been linked with a familial form of early onset pd. in this study, we found that human dj-1 wild type and the missense mutants m26i, r98q, a104t and d149a were stable proteins in cells, only the l166p mutant was unstable. in parallel, the former were not degraded and the l166p mutant was directly degraded in vitro by proteasome-mediated endoproteolytic cleavage. furthermore, genetic ...201122173095
control of mucin-type o-glycosylation - a classification of the polypeptide galnac-transferase gene family.glycosylation of proteins is an essential process in all eukaryotes and a great diversity in types of protein glycosylation exists in animals, plants and microorganisms. mucin-type o-glycosylation, consisting of glycans attached via o-linked galnac to ser and thr residues, is one of the most abundant forms of protein glycosylation in animals. while most protein glycosylation is controlled by one or two genes encoding the enzymes responsible for initiation of glycosylation, i.e. the step where th ...201122183981
Copper Chaperone-Dependent and -Independent Activation of Three Copper-Zinc Superoxide Dismutase Homologs Localized in Different Cellular Compartments in Arabidopsis.Superoxide dismutases (SODs) are important antioxidant enzymes that catalyze the disproportionation of superoxide anion to O2 and H2O2 to guard cells against superoxide toxicity. The major pathway for activation of Cu-Zn SOD (CuZnSOD; CSD) involves a Cu chaperone for SOD (CCS) and an additional minor CCS-independent pathway reported in mammals. We characterized the CCS-dependent and -independent activation pathways for three CSDs localized in different cellular compartments in Arabidopsis thalia ...201122186608
The Human Nucleolar Protein FTSJ3 Associates with NIP7 and Functions in Pre-rRNA Processing.NIP7 is one of the many trans-acting factors required for eukaryotic ribosome biogenesis, which interacts with nascent pre-ribosomal particles and dissociates as they complete maturation and are exported to the cytoplasm. By using conditional knockdown, we have shown previously that yeast Nip7p is required primarily for 60S subunit synthesis while human NIP7 is involved in the biogenesis of 40S subunit. This raised the possibility that human NIP7 interacts with a different set of proteins as com ...201122195017
studies on differential nuclear translocation mechanism and assembly of the three subunits of the arabidopsis thaliana transcription factor nf-y.the eukaryotic transcription factor nf-y consists of three subunits (a, b, and c), which are encoded in arabidopsis thaliana in multigene families consisting of 10, 13, and 13 genes, respectively. in principle, all potential combinations of the subunits are possible for the assembly of the heterotrimeric complex. we aimed at assessing the probability of each subunit to participate in the assembly of nf-y. the evaluation of physical interactions among all members of the nf-y subunit families indi ...201122199235
the effects of the influence of pretreating serum samples on the performance of a latex agglutination test for serodiagnosis of paracoccidioidomycosis.paracoccidioidomycosis (pcm) is a fungal disease caused by paracoccidioides brasiliensis, and brazil is one of its principal endemic countries. diagnosis is based on the observation of budding yeast in clinical specimens from patients; however, the sensitivity of the visualization of fungi is low, indicating that serologic tests are used for early diagnosis. the double-immunodiffusion test (id) is the gold standard test for serology in pcm; although, the execution of this test requires the avail ...201122205661
Toxoplasma gondii Sis1-like J-domain protein is a cytosolic chaperone associated to HSP90/HSP70 complex.Toxoplasma gondii is an obligate intracellular protozoan parasite in which 36 predicted Hsp40 family members were identified by searching the T. gondii genome. The predicted protein sequence from the gene ID TGME49_065310 showed an amino acid sequence and domain structure similar to Saccharomyces cerevisiae Sis1. TgSis1 did not show differences in its expression profile during alkaline stress by microarray analysis. Furthermore, TgSis1 showed to be a cytosolic Hsp40 which co-immunoprecipitated w ...201122209934
help3 directly modulates the expression of hsp70 gene in hela cells via hat activity.human elongator complex, which plays a key role in transcript elongation in vitro assay, is incredibly similar in either components or function to its yeast counterpart. however, there are only a few studies focusing on its target gene characterization in vivo. we studied the effect of down-regulation of the human elongation protein 3 (help3) on the expression of hsp70 through antisense strategy. transfecting antisense plasmid p1107 into hela cells highly suppressed help3 expression, and substan ...201122216241
safety evaluation of a proprietary food-grade, dried fermentate preparation of saccharomyces cerevisiae.a safety evaluation was performed for epicor, a product produced by a proprietary fermentation process using saccharomyces cerevisiae. studies included the following assays: bacterial reverse mutation, mouse lymphoma cell mutagenicity, mitogenicity assay in human peripheral lymphocytes, and a cytochrome p450 ([cyp] cyp1a2 and cyp3a4) induction assessment as well as 14-day acute, 90-day subchronic, and 1-year chronic oral toxicity studies in rats. no evidence of genotoxicity or mitogenicity was s ...201222222580
target-binding proteins based on the 10th human fibronectin type iii domain ((10)fn3).we describe concepts and methods for generating a family of engineered target-binding proteins designed on the scaffold of the 10th human fibronectin type iii domain ((10)fn3), an extremely stable, single-domain protein with an immunoglobulin-like fold but lacking disulfide bonds. large libraries of possible target-binding proteins can be constructed on the (10)fn3 scaffold by diversifying the sequence and length of its surface loops, which are structurally analogous to antibody complementarity- ...201222230568
structure of hdac3 bound to co-repressor and inositol tetraphosphate.histone deacetylase enzymes (hdacs) are emerging cancer drug targets. they regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. the enzymatic activity of most class i hdacs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. here we report the structure of a complex between an hdac and a co-repressor, namely, human hdac3 with the deac ...201222230954
a novel antirecombinase gains parity.in this issue, moldovan et al. (2012) report the identification of pari, a putative human ortholog of the yeast srs2 protein, which potentially regulates homologous recombination repair via its ability to disrupt the function of rad51.201222244326
structure-based alteration of substrate specificity and catalytic activity of sulfite oxidase from sulfite oxidation to nitrate reduction †eukaryotic sulfite oxidase is a dimeric protein that contains the molybdenum cofactor and catalyzes the metabolically essential conversion of sulfite to sulfate as the terminal step in the metabolism of cysteine and methionine. nitrate reductase is an evolutionally related molybdoprotein in lower organisms that is essential for growth on nitrate. in this study we describe human and chicken sulfite oxidase variants in which the active site has been modified to alter substrate specificity and act ...201222263579
chemical reactivity and microbicidal action of bethoxazin.bethoxazin is a new broad spectrum industrial microbicide with applications in material and coating preservation. however, little is known of its reactivity profile and mechanism of action. in this study, we examined the reactivity of bethoxazin toward biologically important nucleophilic groups using uv-vis spectroscopy and lc-ms/ms techniques and found the molecule to be highly electrophilic. bethoxazin reacted with molecules containing free sulfhydryl groups such as gsh and human serum albumin ...201222264763
caffeine abolishes the ultraviolet-induced rev3 translesion replication pathway in mouse cells.when a replicative dna polymerase stalls upon encountering a photoproduct on the template strand, it is relieved by other low-processivity polymerase(s), which insert nucleotide(s) opposite the lesion. using an alkaline sucrose density gradient sedimentation technique, we previously classified this process termed uv-induced translesion replication (uv-tls) into two types. in human cancer cells or xeroderma pigmentosum variant (xp-v) cells, uv-tls was inhibited by caffeine or proteasome inhibitor ...201122272088
roles of candida albicans gat2, a gata-type zinc finger transcription factor, in biofilm formation, filamentous growth and virulence.candida albicans is the most common human fungal pathogen, causing not only superficial infections, but also life-threatening systemic disease. c. albicans can grow in several morphological forms including unicellular yeast-form, elongated hyphae and pseudohyphae. in certain natural environments, c. albicans also exists as biofilms, which are structured and surface-attached microbial communities. transcription factors play a critical role in morphogenesis and biofilm development. in this study, ...201222276126
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