Journal of Biological Chemistry Impact Factor & Information

Publisher: American Society for Biochemistry and Molecular Biology, American Society for Biochemistry and Molecular Biology

Journal description

Complete content of the Journal of Biological Chemistry as of April 1995.

Current impact factor: 4.57

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 4.573
2013 Impact Factor 4.6
2012 Impact Factor 4.651
2011 Impact Factor 4.773
2010 Impact Factor 5.328
2009 Impact Factor 5.328
2008 Impact Factor 5.52
2007 Impact Factor 5.581
2006 Impact Factor 5.808
2005 Impact Factor 5.854
2004 Impact Factor 6.355
2003 Impact Factor 6.482
2002 Impact Factor 6.696
2001 Impact Factor 7.258
2000 Impact Factor 7.368
1999 Impact Factor 7.666
1998 Impact Factor 7.199
1997 Impact Factor 6.963
1996 Impact Factor 7.452
1995 Impact Factor 7.385
1994 Impact Factor 7.716
1993 Impact Factor 6.793
1992 Impact Factor 6.733

Impact factor over time

Impact factor

Additional details

5-year impact 4.69
Cited half-life >10.0
Immediacy index 0.89
Eigenfactor 0.54
Article influence 1.74
Website Journal of Biological Chemistry website
Other titles Journal of biological chemistry (Online), Journal of biological chemistry, JBC online, JBC
ISSN 1083-351X
OCLC 32808313
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

American Society for Biochemistry and Molecular Biology

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Authors accepted peer-reviewed manuscript may be posted on an institutional repository
    • Publisher copyright and source must be acknowledged with set phrase: "This research was originally published in Journal Name. Author(s). Title. Journal Name. Year. Vol:pp-pp. © the American Society for Biochemistry and Molecular Biology"
    • On a non-profit server
    • Publisher's version/PDF cannot be used
  • Classification

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Splicing patterns in HIV-1 are maintained through cis regulatory elements that recruit antagonistic host RNA binding proteins. The activity of the 3 prime acceptor site A7 is tightly regulated through a complex network of an intronic splicing silencer (ISS), a bipartite exonic splicing silencer (ESS3a/b) and an exonic splicing enhancer (ESE3). Since HIV-1 splicing depends on protein-RNA interactions, it is important to know the tertiary structures surrounding the splice sites. Herein, we present the NMR solution structure of the phylogenetically conserved ISS stem loop. ISS adopts a stable structure consisting of conserved UG wobble pairs, a folded 2X2 (GU/UA) internal loop, a UU bulge and a flexible AGUGA apical loop. Calorimetric and biochemical titrations indicate the UP1 domain of hnRNP A1 binds the ISS apical loop site-specifically and with nanomolar affinity. Collectively, this work provides additional insights into how HIV-1 uses a conserved RNA structure to commandeer a host RNA binding protein.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.674564
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    ABSTRACT: Some of the most prevalent neurodegenerative diseases are characterized by the accumulation of amyloid fibrils in organs and tissues. While the pathogenic role of these fibrils is not totally established, increasing evidences suggest off-pathway aggregation (OPA) as a source of toxic/detoxicating deposits that still remains to be targeted. The present work is a step ahead towards the development of off-pathway modulators using the same amyloid-specific dyes as those conventionally employed to screen amyloid inhibitors. We identified a series of kinetic signatures revealing the quantitative importance of OPA relatively to amyloid fibrillization; these include non-linear semi-log plots of amyloid progress curves, highly variable endpoint signals and half-life coordinates weakly influenced by concentration. Molecules that attenuate/intensify the magnitude of these signals are considered promising off-pathway inhibitors/promoters. An illustrative example shows that amyloid deposits of lysozyme are only the tip of an iceberg hiding a crowd of insoluble aggregates. Thoroughly validated using advanced microscopy techniques and complementary measurements of Dynamic Light Scattering (DLS), Circular Dichroism (CD) and soluble protein depletion, the new analytical tools are compatible with the high-throughput methods currently employed in drug discovery.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.699348
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    ABSTRACT: Antibodies with conformational specificity are important for detecting and interfering with polypeptide aggregation linked to several human disorders. We are developing a motif-grafting approach for designing lead antibody candidates specific for amyloid-forming polypeptides such as the Alzheimer's peptide (Aβ). This approach involves grafting amyloidogenic peptide segments into the complementarity-determining regions (CDRs) of single-domain (VH) antibodies. Here we have investigated the impact of polar mutations inserted at the edges of a large hydrophobic Aβ42 peptide segment (Aβ residues 17-42) in CDR3 on the solubility and conformational specificity of the corresponding VH domains. We find that VH expression and solubility are strongly enhanced by introducing multiple negatively charged or asparagine residues at the edges of CDR3, while other polar mutations are less effective (glutamine and serine) or ineffective (threonine, lysine and arginine). Moreover, Aβ VH domains with negatively charged CDR3 mutations show significant preference for recognizing Aβ fibrils relative to Aβ monomer, while the same VH domains with other polar CDR3 mutations recognize both Aβ conformers. We observe similar behavior for a VH domain grafted with a large hydrophobic peptide from islet amyloid polypeptide (residues 8-37) that contains negatively charged mutations at the edges of CDR3. These findings highlight the sensitivity of antibody binding and solubility to residues at the edges of CDRs, and provide guidelines for designing other grafted antibody fragments with hydrophobic binding loops.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.682336
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    ABSTRACT: The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo- and hetero-dimers and oligomers, which transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intra-molecular interactions of syndecan-2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe169 in syndecan TMD. Replacement of SDC2-Phe169 by tyrosine (S2F169Y) did not affect sodium dodecyl sulfate (SDS)-resistant homo-dimer formation, but significantly reduced SDS-resistant heterodimer formation between syndecans-2 and -4, suggesting that SDC2-Phe169 is involved in the hetero-dimerization/oligomerization of syndecans. Similarly, in in vitro binding assay, syndecan-2 mutant [S2(F169Y)] showed a significantly reduced interaction with syndecan-4. Fluorescence resonance energy transfer (FRET) assays showed that hetero-molecular interactions between syndecans-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the hetero-dimerization of syndecans-2 and -4, including Rac activity, cell migration, membrane localization of PKCα and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed hetero-dimeric interaction with syndecans-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.685040
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    ABSTRACT: The synthesis of selenocysteine, the 21st amino acid occurs on its transfer RNA (tRNA), tRNASec. tRNASec is initially aminoacylated with serine by seryl-tRNA synthetase and the resulting seryl moiety is converted to phosphoserine by O-phosphoseryl-tRNA kinase (PSTK) in eukaryotes. The selenium donor, selenophosphate is synthesized from selenide and ATP by selenophosphate synthetase. Selenocysteinyl-tRNA synthase (SepSecS) then uses the O-phosphoseryl-tRNASec and selenophosphate, to form Sec-tRNASec in eukaryotes. Here, we report the characterization of selenocysteinyl-tRNA synthase from L. donovani. Kinetoplastid SepSecS enzymes are phylogenetically closer to worm SepSecS. LdSepSecS was found to exist as a tetramer. Leishmania SepSecS enzyme was found to be active and able to complement the ∆selA deletion in E. coli JS1 strain only in the presence of archaeal PSTK, indicating the conserved nature of the PSTK-SepSecS pathway. LdSepSecS was found to localize in the cytoplasm of the parasite. Gene deletion studies indicate that Leishmania SepSecS is dispensable for the parasite survival. The parasite was found to encode three selenoproteins; which expressed only in the presence of SepSecS. Selenoproteins of L. donovani are not required for the growth of the promastigotes. Auranofin, a known inhibitor of selenoprotein synthesis showed same sensitivity towards the wild-type and the null mutants suggesting its effect is not through binding to selenoproteins. The 3-D structural comparison indicates that the human and Leishmania homologs are structurally highly similar but their association modes leading to tetramerization seem different.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.695007
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    ABSTRACT: The interface between relay and converter domain of muscle myosin is critical for optimal myosin performance. Using Drosophila melanogaster indirect flight muscle S1 we performed a kinetic analysis of the effect of mutations in the converter and relay domain. Introduction of a mutation (R759E) in the converter domain inhibits the steady-state ATPase of myosin S1, whereas an additional mutation in the relay domain (N509K) is able to restore the ATPase towards wild-type values. The S1- R759E construct showed little effect on most steps of the actomyosin ATPase cycle. The exception was a 25-30% reduction in the rate constant of the hydrolysis step, the step coupled to the cross-bridge recovery stroke and involving a change in conformation at the relay/converter domain interface. Significantly the double mutant restored the hydrolysis step to values similar to the wild-type myosin. Modelling the relay/converter interface suggests a possible interaction between converter residue 759 and relay residue 509 in the actin-detached conformation, which is lost in R759E but is restored in N509K/R759E. This detailed kinetic analysis of Drosophila myosin carrying the R759E mutation shows that the interface between the relay loop and converter domain is important for fine-tuning myosin kinetics, in particular ATP-binding and hydrolysis.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.688002
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    ABSTRACT: To translate the thirteen mtDNA-encoded mRNAs involved in oxidative phosphorylation (OXPHOS), mammalian mitochondria contain a dedicated set of ribosomes comprising rRNAs encoded by the mitochondrial genome and mitochondrial ribosomal proteins (MRPs) that are encoded by nuclear genes and imported into the matrix. In addition to their role in the ribosome, several MRPs have auxiliary functions or have been implicated in other cellular processes like cell cycle regulation and apoptosis. For example, we have shown that human MRPL12 binds and activates mitochondrial RNA polymerase (POLRMT), and hence has distinct functions in the ribosome and mtDNA transcription. Here we provide concrete evidence that there are two mature forms of mammalian MRPL12 that are generated by a two-step cleavage during import, involving efficient cleavage by mitochondrial processing protease (MPP) and a second inefficient or regulated cleavage by mitochondrial intermediary protease (MIP). We also show that knock-down of MRPL12 by RNAi results in instability of POLRMT, but not other primary mitochondrial transcription components, and a corresponding decrease in mitochondrial transcription rates. Knock-down of MRPL10, the binding partner of MRPL12 in the ribosome, results in selective degradation of the mature long form of MRPL12, but has no effect on POLRMT. We propose that the two forms of MRPL12 are involved in homeostatic regulation of mitochondrial transcription and ribosome biogenesis that likely contribute to cell cycle, growth regulation and longevity pathways to which MRPL12 has been linked.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.689299
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    ABSTRACT: We recently reported that an amide bond is unexpectedly formed by an acyl-CoA synthetase (which catalyzes the formation of a carbon-sulfur bond) when a suitable acid and L-cysteine are used as substrates. DltA, which is homologous to the adenylation domain of nonribosomal peptide synthetase, belongs to the same superfamily of adenylate-forming enzymes, which comprises many kinds of enzymes including the acyl-CoA synthetases. Here, we demonstrate that DltA synthesizes not only N-(D-alanyl)-L-cysteine (a dipeptide) but also various oligopeptides. We propose that this enzyme catalyzes peptide synthesis by the following unprecedented mechanism: (i) the formation of S-acyl-L-cysteine as an intermediate via its "enzymatic activity" and (ii) subsequent "chemical" S→N acyl transfer in the intermediate, resulting in peptide formation. Step (ii) is identical to the corresponding reaction in native chemical ligation (NCL), a method of chemical peptide synthesis, whereas step (i) is not. To the best of our knowledge, our discovery of this peptide synthesis mechanism involving an enzymatic reaction and a subsequent chemical reaction is the first such one to be reported. This new process yields peptides without the use of a thioesterified fragment, which is required in NCL. Together with these findings, the same mechanism-dependent formation of N-acyl-compounds by other members of the above-mentioned superfamily demonstrated that all members most likely form peptide/amide compounds by using this novel mechanism. Each member enzyme acts on a specific substrate, thus, not only the corresponding peptides but also new types of amide compounds can be formed.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.700989
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    ABSTRACT: Advanced glycation end products (AGE) accumulate in diabetic patients and aging people due to high amounts of 3- or 4-carbon sugars derived from glucose and thereby causing multiple consequences including inflammation, apoptosis, obesity and age-related disorders. It is important to understand the mechanism of AGE-mediated signaling leading to activation of autophagy (self-eating) that might result in obesity. We have detected AGE as one of the potent inducers of autophagy compared to doxorubicin and TNF. AGE-mediated autophagy is inhibited by suppression of PI3 kinase and potentiated by autophagosome maturation blocker, bafilomycin. It increases autophagy in different cell types and that correlates with the expression of it receptor, RAGE. LC3B, the marker for autophagosome is shown to increase upon AGE stimulation. AGE-mediated autophagy is suppressed partially by inhibitor of NF-κB, PKC, or ERK alone and significantly in combination. AGE increases SREBP activity that leads to increase in lipogenesis. Though AGE-mediated lipogenesis is affected by autophagy inhibitor, AGE-mediated autophagy is not influenced by lipogenesis inhibitor, suggesting that the turnover of lipid droplets overcomes the autophagic clearance. For the first time, we are providing data that AGE induces several cell signaling cascades, like NF-κB, PKC, ERK, and MAPK, which are involved in autophagy and simultaneously help in accumulating lipid droplets which are not effectively cleared by autophagy, thus follows obesity.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.667576
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    ABSTRACT: Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with Ceacam2 null mutation (Cc2-/-). The current studies investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in beta cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-beta cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2-/- islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2-/- mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared to wild type, Cc2-/- mice also showed a higher insulin excursion during oral glucose tolerance test. Pretreating with exendin (9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag entero-endocrine cells was increased with siRNA-mediated Ceacam2 downregulation in parallel to increase in Ca2+ entry through L-type voltage-dependent Ca2+ channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1 mediated mechanism, independent of confounding metabolic factors.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.692582
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    ABSTRACT: We previously showed that galectin-9 suppresses degranulation of mast cells through protein-glycan interaction with IgE. To elucidate the mechanism of the interaction in detail, we focused on identification and structural analysis of IgE glycans responsible for the galectin-9-induced suppression using mouse monoclonal IgE (TIB-141). TIB-141 in combination with the antigen induced degranulation of RBL-2H3 cells, which was almost completely inhibited by human and mouse galectin-9. Sequential digestion of TIB-141 with lysyl endopeptidase and trypsin resulted in the identification of a glycopeptide (H-Lys13-Try3; 48 amino acid residues) with a single N-linked oligosaccharide near the N-terminus capable of neutralizing the effect of galectin-9 and another glycopeptide with two N-linked oligosaccharides (H-Lys13-Try1; 16 amino acid residues) having lower activity. Enzymatic elimination of the oligosaccharide chain from H-Lys13-Try3 and H-Lys13-Try1 completely abolished the activity. Removal of the carboxy-terminal 38 amino acid residues of H-Lys13-Try3 with glutamyl endopeptidase, however, also resulted in loss of the activity. We determined the structures of N-linked oligosaccharides of H-Lys13-Try1. The galectin-9-binding fraction of oligosaccharides released with peptide-N-glycosidase F contained asialo- and mono-sialylated bi/tri-antennary complex-type oligosaccharides with a core fucose residue. The structures of the oligosaccharides were consistent with the sugar-binding specificity of galectin-9, while the nonbinding fraction contained monosialylated and disialylated biantennary complex-type oligosaccharides with a core fucose residue. Although the oligosaccharides linked to H-Lys13-Try3 could not be fully characterized, these results indicate the possibility that cooperative binding of oligosaccharide and neighboring polypeptide structures of TIB-141 to galectin-9 affects the overall affinity and specificity of the IgE-lectin interaction.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.694448
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    ABSTRACT: Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-EdU incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of approximately 80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta-cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.687848
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    ABSTRACT: The eukaryotic translation initiation factor (eIF) 4G is required during protein synthesis to promote the assembly of several factors involved in the recruitment of a 40S ribosomal subunit to an mRNA. Although many eukaryotes express two eIF4G isoforms that are highly similar, the eIF4G isoforms in plants, referred to as eIF4G and eIFiso4G, are highly divergent in size, sequence, and domain organization but both can interact with eIF4A, eIF4B, eIF4E isoforms, and the poly(A)-binding protein. Nevertheless, eIF4G and eIFiso4G from wheat exhibit preferences in the mRNAs they translate optimally. For example, mRNA containing the 5'-leader (called Ω) of tobacco mosaic virus (TMV) preferentially uses eIF4G in wheat germ lysate. In this study, the eIF4G isoform specificity of Ω was used to examine functional differences of the eIF4G isoforms in Arabidopsis. As in wheat, Ω-mediated translation was reduced in an eif4g null mutant. Loss of the eIFiso4G1 isoform, which is similar in sequence to wheat eIFiso4G, did not substantially affect Ω-mediated translation. However, loss of the eIFiso4G2 isoform substantially reduced Ω-mediated translation. eIFiso4G2 is substantially divergent from eIFiso4G1 and is present only in the Brassicaceae, suggesting a recent evolution. eIFiso4G2 isoforms exhibit sequence-specific differences in regions representing partner protein and RNA binding sites. Loss of any eIF4G isoform also resulted in a substantial reduction in reporter transcript level. These results suggest that eIFiso4G2 appeared late in plant evolution and exhibits more functional similarity with eIF4G than with eIFiso4G1 during Ω-mediated translation.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.692939
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    ABSTRACT: Excessive release of Zn(2+) in the brain is implicated in the progression of acute brain injuries. Although several signaling cascades have been reported to be involved in Zn(2+)-induced neurotoxicity, a potential contribution of tyrosine phosphatases in this process has not been well explored. Here we show that exposure to high concentrations of Zn(2+) led to a progressive increase in phosphorylation of the striatal-enriched phosphatase (STEP), a component of the excitotoxic-signaling pathway that plays a role in neuroprotection. Zn(2+) mediated phosphorylation of STEP61 at multiple sites (hyperphosphorylation) was induced by the up-regulation of brain-derived neurotropic factor (BDNF), tropomyosin receptor kinase (Trk) signaling and activation of cAMP-dependent PKA (protein kinase A). Mutational studies further showed that differential phosphorylation of STEP61 at the PKA sites, ser160 and ser221 regulates the affinity of STEP61 towards its substrates. Consistent with these findings we also show that BDNF/Trk/PKA mediated signaling is required for Zn(2+)-induced phosphorylation of extracellular regulated kinase 2 (ERK2), a substrate of STEP that is involved in Zn(2+)-dependent neurotoxicity. The strong correlation between the temporal profile of STEP61 hyperphosphorylation and ERK2 phosphorylation indicates that loss of function of STEP61 through phosphorylation is necessary for maintaining sustained ERK2 phosphorylation. This interpretation is further supported by the findings that deletion of the STEP gene led to a rapid and sustained increase in ERK2 phosphorylation within minutes of exposure to Zn(2+). The study provides further insight into the mechanisms of regulation of STEP61 and also offers a molecular basis for the Zn(2+)-induced sustained activation of ERK2.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.663468
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    ABSTRACT: Dynamic regulation of endothelial cell adhesion is central to vascular development and maintenance. Furthermore, altered endothelial adhesion is implicated in numerous diseases. Thus, normal vascular patterning and maintenance require tight regulation of endothelial cell adhesion dynamics. Yet, the mechanisms that control junctional plasticity are not fully understood. VE-cadherin is an adhesive protein found in adherens junctions of endothelial cells. VE-cadherin mediates adhesion through trans interactions formed by its extracellular domain. Trans binding is followed by cis interactions that laterally cluster the cadherin in junctions. VE-cadherin is linked to the actin cytoskeleton through cytoplasmic interactions with β and α-catenin, which serve to increase adhesive strength. Furthermore, p120-catenin binds to the cytoplasmic tail of the cadherin and stabilizes it at the plasma membrane. Here, we report that induced cis-dimerization of VE-cadherin inhibits endocytosis independent of both p120 binding and trans interactions. However, we find that ankyrin-G, a protein that links membrane proteins to the spectrin-actin cytoskeleton, associates with VE-cadherin and inhibits its endocytosis. Ankyrin-G inhibits VE-cadherin endocytosis independent of p120 binding. We propose a model in which ankyrin-G associates with and inhibits the endocytosis of VE-cadherin cis-dimers. Our findings support a novel mechanism for regulation of VE-cadherin endocytosis through ankyrin association with cadherin engaged in lateral interactions.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.648386
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    ABSTRACT: Viruses have developed distinct strategies to overcome the host defense system. Regulation of apoptosis in response to viral infection is important for virus survival and dissemination. Like other viruses, Crimean-Congo hemorrhagic fever virus (CCHFV) is known to regulate apoptosis. This study for the first time suggests that the non-structural protein NSs of CCHFV, a member of the genus Nairovirus, induces apoptosis. In this report, we demonstrated the expression of CCHFV NSs, which contains 150 amino acid (aa) residues, in the CCHFV-infected cells. CCHFV NSs undergoes active degradation during infection. We further demonstrated that ectopic expression of CCHFV NSs induces apoptosis, as reflected by the caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase (PARP), in different cell lines that support CCHFV replication. Using specific inhibitors, we showed that CCHFV NSs induces apoptosis via both intrinsic and extrinsic pathways. The minimal active region of the CCHFV NSs protein was determined to be 93-140 aa residues. Using alanine scanning, we demonstrated that L127 and L135 are the key residues for NSs-induced apoptosis. Interestingly, CCHFV NSs co-localizes in mitochondria and also disrupts the mitochondrial membrane potential. We also demonstrated that L127 and L135 are important residues for the disruption of mitochondrial membrane potential by NSs. Thus, these results indicate that the C-terminal of CCHFV NSs triggers mitochondrial membrane permeabilization leading to activation of caspases which ultimately leads to apoptosis. Given that multiple factors contribute to apoptosis during CCHFV infection, further studies are needed to define the involvement of CCHFV NSs in regulating apoptosis in infected cells.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.667436
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    ABSTRACT: In response to environmental cues, the MAP kinase Sty1-driven signaling cascade activates hundreds of genes to induce a robust anti-stress cellular response in fission yeast. Thus, upon stress imposition Sty1 transiently accumulates in the nucleus where it up-regulates transcription through the Atf1 transcription factor. Several regulators of transcription and translation have been identified as important to mount an integral response to oxidative stress, such as the SAGA or Elongator complexes, respectively. With the aim of identifying new regulators of this massive gene expression program, we have used a GFP-based protein reporter and screened a fission yeast deletion collection using flow cytometry. We find that the levels of catalase fused to GFP, both before and after a threat of peroxides, are altered in hundreds of strains lacking components of chromatin modifiers, transcription complexes and modulators of translation. Thus, the transcription elongation complex Paf1, the histone methylase Set1-COMPASS and the translation-related Trm112 dimers are all involved in full expression of Ctt1-GFP and in wild-type tolerance to peroxides.
    Journal of Biological Chemistry 11/2015; DOI:10.1074/jbc.M115.696658