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Amyloid-β Peptide Binds to Cytochrome C Oxidase Subunit 1  [PDF]
Luis Fernando Hernandez-Zimbron, Jose Luna-Mu?oz, Raul Mena, Ricardo Vazquez-Ramirez, Carlos Kubli-Garfias, David H. Cribbs, Karen Manoutcharian, Goar Gevorkian
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042344
Abstract: Extracellular and intraneuronal accumulation of amyloid-beta aggregates has been demonstrated to be involved in the pathogenesis of Alzheimer's disease (AD). However, the precise mechanism of amyloid-beta neurotoxicity is not completely understood. Previous studies suggest that binding of amyloid-beta to a number of macromolecules has deleterious effects on cellular functions. Mitochondria were found to be the target for amyloid-beta, and mitochondrial dysfunction is well documented in AD. In the present study we have shown for the first time that Aβ 1–42 bound to a peptide comprising the amino-terminal region of cytochrome c oxidase subunit 1. Phage clone, selected after screening of a human brain cDNA library expressed on M13 phage and bearing a 61 amino acid fragment of cytochrome c oxidase subunit 1, bound to Aβ 1–42 in ELISA as well as to Aβ aggregates present in AD brain. Aβ 1–42 and cytochrome c oxidase subunit 1 co-immunoprecipitated from mitochondrial fraction of differentiated human neuroblastoma cells. Likewise, molecular dynamics simulation of the cytochrome c oxidase subunit 1 and the Aβ 1–42 peptide complex resulted in a reliable helix-helix interaction, supporting the experimental results. The interaction between Aβ 1–42 and cytochrome c oxidase subunit 1 may explain, in part, the diminished enzymatic activity of respiratory chain complex IV and subsequent neuronal metabolic dysfunction observed in AD.
Histone variants: are they functionally heterogeneous?
David T Brown
Genome Biology , 2001, DOI: 10.1186/gb-2001-2-7-reviews0006
Abstract: The basic subunit of eukaryotic chromatin is the nucleosome [1,2]. Two molecules of each of the core histone proteins - H2A, H2B, H3 and H4 - form an octamer, the protein component of the nucleosome core particle, around which 147 basepairs of DNA are wrapped. One histone molecule of the linker or H1 class binds to the octamer near the point where the DNA enters and exits the nucleosome and seals two full turns (approximately 166 basepairs) of DNA around the octamer [3]. Histone H1 also associates with linker DNA between nucleosomes to stabilize higher-order structures. As nucleosomal structure is similar in all metazoans, it is not surprising that histones are among the most highly conserved proteins in terms of both structure and sequence. But in higher organisms each histone subtype, with the possible exception of histone H4, is represented by a family of genes encoding multiple non-allelic primary-sequence variants [1,2,3,4,5]. Why should this be the case?There are several plausible explanations for the existence of multiple histone-encoding genes [4,5,6]. The first is simply gene dosage. A demand for high gene expression at specific times might require multiple active transcriptional units - for example, in the case of histones large amounts are needed during S phase when DNA is replicated and packaged into nucleosomes. In this case, heterogeneity at the protein-sequence level may be the result of genetic drift and would be of little consequence. An extension of this view might include heterogeneity at the level of regulation: multiple histone genes with distinct expression patterns during differentiation, in specific tissues, or under certain metabolic conditions might be necessary to ensure that adequate amounts of each histone are present in all cells. Evidence for this in higher organisms comes from the presence of replacement variants that, unlike most other histones, are expressed throughout the cell cycle and serve as a source of chromatin components nee
The histone chaperone protein Nucleosome Assembly Protein-1 (hNAP-1) binds HIV-1 Tat and promotes viral transcription
Chiara Vardabasso, Lara Manganaro, Marina Lusic, Alessandro Marcello, Mauro Giacca
Retrovirology , 2008, DOI: 10.1186/1742-4690-5-8
Abstract: Using a proteomic screening, we identified hNAP-1 as a novel cellular protein interacting with HIV-1 Tat. We observed that Tat specifically binds hNAP1, but not other members of the same family of factors. Binding between the two proteins required the integrity of the basic domain of Tat and of two separable domains of hNAP-1 (aa 162–290 and 290–391). Overexpression of hNAP-1 significantly enhanced Tat-mediated activation of the LTR. Conversely, silencing of the protein decreased viral promoter activity. To explore the effects of hNAP-1 on viral infection, a reporter HIV-1 virus was used to infect cells in which hNAP-1 had been either overexpressed or knocked-down. Consistent with the gene expression results, these two treatments were found to increase and inhibit viral infection, respectively. Finally, we also observed that the overexpression of p300, a known co-activator of both Tat and hNAP-1, enhanced hNAP-1-mediated transcriptional activation as well as its interaction with Tat.Our study reveals that HIV-1 Tat binds the histone chaperone hNAP-1 both in vitro and in vivo and shows that this interaction participates in the regulation of Tat-mediated activation of viral gene expression.Efficient packaging of DNA in a highly organized chromatin structure inside the cell is one of the most remarkable characteristics of all eukaryotic organisms. Chromatin assembly and disassembly are dynamic biological processes that increase chromatin fluidity and regulate the accessibility of the genome to all DNA transactions, including transcription, DNA replication and DNA repair. The basic structural unit of eukaryotic chromatin is the nucleosome, formed by the wrapping of DNA around an octamer of core histone proteins. By restricting the access to DNA-binding factors and impeding elongation by RNA polymerase II (RNAPII), the nucleosome is not only a structural unit of the chromosome, but perhaps the most important regulator of gene expression (for recent reviews, see refs. [1,
Modulation of Cell Adhesion and Migration by the Histone Methyltransferase Subunit mDpy-30 and Its Interacting Proteins  [PDF]
Bin Xia,Alexandra Joubert,Benjamin Groves,Kevin Vo,Davin Ashraf,Derek Djavaherian,Jason Awe,Ying Xiong,Jacqueline Cherfils,Dzwokai Ma
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011771
Abstract: We have previously shown that a subset of mDpy-30, an accessory subunit of the nuclear histone H3 lysine 4 methyltransferase (H3K4MT) complex, also localizes at the trans-Golgi network (TGN), where its recruitment is mediated by the TGN-localized ARF guanine nucleotide exchange factor (ArfGEF) BIG1. Depletion of mDpy-30 inhibits the endosome-to-TGN transport of internalized CIMPR receptors and concurrently promotes their accumulation at the cell protrusion. These observations suggest mDpy-30 may play a novel role at the crossroads of endosomal trafficking, nuclear transcription and adhesion/migration. Here we provide novel mechanistic and functional insight into this association. First, we demonstrate a direct interaction between mDpy-30 and BIG1 and locate the binding region in the N-terminus of BIG1. Second, we provide evidence that the depletion or overexpression of mDpy-30 enhances or inhibits cellular adhesion/migration of glioma cells in vitro, respectively. A similar increase in cell adhesion/migration is observed in cells with reduced levels of BIG1 or other H3K4MT subunits. Third, knockdown of mDpy-30, BIG1, or the RbBP5 H3K4MT subunit increases the targeting of β1 integrin to cell protrusions, and suppression of H3K4MT activity by depleting mDpy-30 or RbBP5 leads to increased protein and mRNA levels of β1 integrin. Moreover, stimulation of cell adhesion/migration via mDpy-30 knockdown is abolished after treating cells with a function-blocking antibody to β1 integrin. Taken together, these data indicate that mDpy-30 and its interacting proteins function as a novel class of cellular adhesion/migration modulators partially by affecting the subcellular distribution of endosomal compartments as well as the expression of key adhesion/migration proteins such as β1 integrin.
The eEF1γ Subunit Contacts RNA Polymerase II and Binds Vimentin Promoter Region  [PDF]
Nicoletta Corbi,Enrico Maria Batassa,Cinzia Pisani,Annalisa Onori,Maria Grazia Di Certo,Georgios Strimpakos,Maurizio Fanciulli,Elisabetta Mattei,Claudio Passananti
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014481
Abstract: Here, we show that the eukaryotic translation elongation factor 1 gamma (eEF1γ) physically interacts with the RNA polymerase II (pol II) core subunit 3 (RPB3), both in isolation and in the context of the holo-enzyme. Importantly, eEF1γ has been recently shown to bind Vimentin mRNA. By chromatin immunoprecipitation experiments, we demonstrate, for the first time, that eEF1γ is also physically present on the genomic locus corresponding to the promoter region of human Vimentin gene. The eEF1γ depletion causes the Vimentin protein to be incorrectly compartmentalised and to severely compromise cellular shape and mitochondria localisation. We demonstrate that eEF1γ partially colocalises with the mitochondrial marker Tom20 and that eEF1γ depletion increases mitochondrial superoxide generation as well as the total levels of carbonylated proteins. Finally, we hypothesise that eEF1γ, in addition to its role in translation elongation complex, is involved in regulating Vimentin gene by contacting both pol II and the Vimentin promoter region and then shuttling/nursing the Vimentin mRNA from its gene locus to its appropriate cellular compartment for translation.
Trimeric Form of Intracellular ATP Synthase Subunit β of Aggregatibacter actinomycetemcomitans Binds Human Interleukin-1β  [PDF]
Annamari Paino,Heidi Tuominen,Mari J??skel?inen,Jonna Alanko,Jari Nuutila,Sirkka E. Asikainen,Lauri J. Pelliniemi,Marja T. P?ll?nen,Casey Chen,Riikka Ihalin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018929
Abstract: Bacterial biofilms resist host defenses and antibiotics partly because of their decreased metabolism. Some bacteria use proinflammatory cytokines, such as interleukin (IL)-1β, as cues to promote biofilm formation and to alter virulence. Although one potential bacterial IL-1β receptor has been identified, current knowledge of the bacterial IL-1β sensing mechanism is limited. In chronic biofilm infection, periodontitis, Aggregatibacter actinomycetemcomitans requires tight adherence (tad)-locus to form biofilms, and tissue destroying active lesions contain more IL-1β than inactive ones. The effect of IL-1β on the metabolic activity of A. actinomycetemcomitans biofilm was tested using alamarBlue?. The binding of IL-1β to A. actinomycetemcomitans cells was investigated using transmission electron microscopy and flow cytometry. To identify the proteins which interacted with IL-1β, different protein fractions from A. actinomycetemcomitans were run in native-PAGE and blotted using biotinylated IL-1β and avidin-HRP, and identified using mass spectroscopy. We show that although IL-1β slightly increases the biofilm formation of A. actinomycetemcomitans, it reduces the metabolic activity of the biofilm. A similar reduction was observed with all tad-locus mutants except the secretin mutant, although all tested mutant strains as well as wild type strains bound IL-1β. Our results suggest that IL-1β might be transported into the A. actinomycetemcomitans cells, and the trimeric form of intracellular ATP synthase subunit β interacted with IL-1β, possibly explaining the decreased metabolic activity. Because ATP synthase is highly conserved, it might universally enhance biofilm resistance to host defense by binding IL-1β during inflammation.
The UBC9 E2 SUMO Conjugating Enzyme Binds the PR-Set7 Histone Methyltransferase to Facilitate Target Gene Repression  [PDF]
Tanya M. Spektor, Lauren M. Congdon, Chendhore S. Veerappan, Judd C. Rice
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022785
Abstract: PR-Set7/Set8/KMT5a is a chromatin-modifying enzyme that specifically monomethylates lysine 20 of histone H4 (H4K20me1). In this study we attempted to identify PR-Set7-interacting proteins reasoning that these proteins would provide important insights into the role of PR-Set7 in transcriptional regulation. Using an unbiased yeast two-hybrid approach, we discovered that PR-Set7 interacts with the UBC9 E2 SUMO conjugating enzyme. This interaction was confirmed in human cells and we demonstrated that PR-Set7 was preferentially modified with SUMO1 in vivo. Further in vitro studies revealed that UBC9 directly binds PR-Set7 proximal to the catalytic SET domain. Two putative SUMO consensus sites were identified in this region and both were capable of being SUMOylated in vitro. The absence of either or both SUMO sites did not perturb nuclear localization of PR-Set7. By employing whole genome expression arrays, we identified a panel of genes whose expression was significantly altered in the absence of PR-Set7. The vast majority of these genes displayed increased expression strongly suggesting that PR-Set7 predominantly functions as a transcriptional repressor. Importantly, the reduction of UBC9 resulted in the consistent derepression of several of these newly identified genes regulated by PR-Set7. Our findings indicate that direct interaction with UBC9 facilitates the repressive effects of PR-Set7 at specific target genes, most likely by SUMOylating PR-Set7.
Bovine Papillomavirus Type 2 (BPV-2) E5 Oncoprotein Binds to the Subunit D of the V1-ATPase Proton Pump in Naturally Occurring Urothelial Tumors of the Urinary Bladder of Cattle  [PDF]
Sante Roperto, Valeria Russo, Giuseppe Borzacchiello, Chiara Urraro, Roberta Lucà, Iolanda Esposito, Marita Georgia Riccardi, Cinzia Raso, Marco Gaspari, Dora Maria Ceccarelli, Rocco Galasso, Franco Roperto
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088860
Abstract: Background Active infection by bovine papillomavirus type 2 (BPV-2) was documented for fifteen urinary bladder tumors in cattle. Two were diagnosed as papillary urothelial neoplasm of low malignant potential (PUNLMP), nine as papillary and four as invasive urothelial cancers. Methods and Findings In all cancer samples, PCR analysis revealed a BPV-2-specific 503 bp DNA fragment. E5 protein, the major oncoprotein of the virus, was shown both by immunoprecipitation and immunohistochemical analysis. E5 was found to bind to the activated (phosphorylated) form of the platelet derived growth factor β receptor. PDGFβR immunoprecipitation from bladder tumor samples and from normal bladder tissue used as control revealed a protein band which was present in the pull-down from bladder cancer samples only. The protein was identified with mass spectrometry as “V1-ATPase subunit D”, a component of the central stalk of the V1-ATPase vacuolar pump. The subunit D was confirmed in this complex by coimmunoprecipitation investigations and it was found to colocalize with the receptor. The subunit D was also shown to be overexpressed by Western blot, RT-PCR and immunofluorescence analyses. Immunoprecipitation and immunofluorescence also revealed that E5 oncoprotein was bound to the subunit D. Conclusion For the first time, a tri-component complex composed of E5/PDGFβR/subunit D has been documented in vivo. Previous in vitro studies have shown that the BPV-2 E5 oncoprotein binds to the proteolipid c ring of the V0-ATPase sector. We suggest that the E5/PDGFβR/subunit D complex may perturb proteostasis, organelle and cytosol homeostasis, which can result in altered protein degradation and in autophagic responses.
The SUVR4 Histone Lysine Methyltransferase Binds Ubiquitin and Converts H3K9me1 to H3K9me3 on Transposon Chromatin in Arabidopsis  [PDF]
Silje V. Veiseth,Mohummad A. Rahman,Kyoko L. Yap,Andreas Fischer,Wolfgang Egge-Jacobsen,Gunter Reuter,Ming-Ming Zhou,Reidunn B. Aalen,Tage Thorstensen
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001325
Abstract: Chromatin structure and gene expression are regulated by posttranslational modifications (PTMs) on the N-terminal tails of histones. Mono-, di-, or trimethylation of lysine residues by histone lysine methyltransferases (HKMTases) can have activating or repressive functions depending on the position and context of the modified lysine. In Arabidopsis, trimethylation of lysine 9 on histone H3 (H3K9me3) is mainly associated with euchromatin and transcribed genes, although low levels of this mark are also detected at transposons and repeat sequences. Besides the evolutionarily conserved SET domain which is responsible for enzyme activity, most HKMTases also contain additional domains which enable them to respond to other PTMs or cellular signals. Here we show that the N-terminal WIYLD domain of the Arabidopsis SUVR4 HKMTase binds ubiquitin and that the SUVR4 product specificity shifts from di- to trimethylation in the presence of free ubiquitin, enabling conversion of H3K9me1 to H3K9me3 in vitro. Chromatin immunoprecipitation and immunocytological analysis showed that SUVR4 in vivo specifically converts H3K9me1 to H3K9me3 at transposons and pseudogenes and has a locus-specific repressive effect on the expression of such elements. Bisulfite sequencing indicates that this repression involves both DNA methylation–dependent and –independent mechanisms. Transcribed genes with high endogenous levels of H3K4me3, H3K9me3, and H2Bub1, but low H3K9me1, are generally unaffected by SUVR4 activity. Our results imply that SUVR4 is involved in the epigenetic defense mechanism by trimethylating H3K9 to suppress potentially harmful transposon activity.
An MHC-I Cytoplasmic Domain/HIV-1 Nef Fusion Protein Binds Directly to the μ Subunit of the AP-1 Endosomal Coat Complex  [PDF]
Rajendra Kumar Singh,David Lau,Colleen M. Noviello,Partho Ghosh,John C. Guatelli
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008364
Abstract: The down-regulation of the major histocompatibility complex class I (MHC-I) from the surface of infected cells by the Nef proteins of primate immunodeficiency viruses likely contributes to pathogenesis by providing evasion of cell-mediated immunity. HIV-1 Nef-induced down-regulation involves endosomal trafficking and a cooperative interaction between the cytoplasmic domain (CD) of MHC-I, Nef, and the clathrin adaptor protein complex-1 (AP-1). The CD of MHC-I contains a key tyrosine within the sequence YSQA that is required for down-regulation by Nef, but this sequence does not conform to the canonical AP-binding tyrosine-based motif Yxxφ, which mediates binding to the medium (μ) subunits of AP complexes. We previously proposed that Nef allows the MHC-I CD to bind the μ subunit of AP-1 (μ1) as if it contained a Yxxφmotif.
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