Biochemical Journal (BIOCHEM J)

Publisher: Biochemical Society (Great Britain), Portland Press

Journal description

The Biochemical Journal publishes over 7000 pages of high-quality scientific information every year. The papers are carefully selected by an international editorial board to cover all aspects of biochemistry, and cell and molecular biology. The journal features regular papers, authoritative reviews, research communications (short articles reporting novel and significant findings) and correspondence.

Current impact factor: 4.78

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 4.779
2012 Impact Factor 4.654
2011 Impact Factor 4.897
2010 Impact Factor 5.016
2009 Impact Factor 5.155
2008 Impact Factor 4.371
2007 Impact Factor 4.009
2006 Impact Factor 4.1
2005 Impact Factor 4.224
2004 Impact Factor 4.278
2003 Impact Factor 4.101
2002 Impact Factor 4.589
2001 Impact Factor 4.326
2000 Impact Factor 4.28
1999 Impact Factor 4.349
1998 Impact Factor 3.855
1997 Impact Factor 3.579
1996 Impact Factor 3.687
1995 Impact Factor 4.159
1994 Impact Factor 4.262
1993 Impact Factor 3.659
1992 Impact Factor 3.716

Impact factor over time

Impact factor

Additional details

5-year impact 5.02
Cited half-life 0.00
Immediacy index 1.19
Eigenfactor 0.08
Article influence 1.94
Website Biochemical Journal website
Other titles Biochemical journal (London, England: 1984), Biochemical journal
ISSN 0264-6021
OCLC 10379627
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

Portland Press

  • Pre-print
    • Author cannot archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 6 months embargo
  • Conditions
    • On author's personal website or institutional repository
    • Accepted version may be placed on PubMed Central and Europe PMC after 12 months from publication
    • Must link to journal website
    • Published source must be acknowledged ('The final version of record is available at [insert Journals URL]')
    • Publisher's version/PDF cannot be used
    • Must link to journal website, e.g. with a DOI
  • Classification
    ​ white

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The serotonin (5-HT) transporter (SERT) controls serotonergic neurotransmission in the brain by rapid clearance of 5-HT from the synaptic cleft into presynaptic neurons. SERTs are primary target for antidepressants for therapeutic intervention of mood disorders. Our previous studies have identified the involvement of several signaling pathways and protein kinases in regulating SERT function, trafficking and phosphorylation. However, whether the protein kinase B/Akt regulates SERT function is not known. Here, we made novel observation that inhibition of Akt resulted in the down regulation of SERT function through the regulation of SERT trafficking and phosphorylation. Akt inhibitor Akt X reduced the endogenously phosphorylated Akt and significantly decreased 5-HT uptake and 5-HT uptake capacity. Furthermore, SERT activity is also reduced by small interfering RNA downregulation of total and phospho-Akt levels. The reduction in SERT activity is paralleled by lower level of surface SERT protein, reduced SERT exocytosis with no effect on SERT endocytosis and accumulation of SERT in intracellular endocytic compartments with the most prominent localization to late endosomes and lysosomes. Akt2 inhibitor was more effective than Akt1 inhibitor in inhibiting SERT activity. Inhibition of downstream Akt kinase GSK3a/ß stimulates SERT function. Akt inhibition leads to decrease in SERT basal phosphorylation. Our results provide evidence that Akt regulates SERT function and cell surface expression by regulating the intracellular SERT distribution and plasma membrane availability, which perhaps may be linked to SERT phosphorylation state. Thus, any changes in the activation of Akt and/or GSK3a/ß could alter SERT mediated 5-HT clearance and subsequently serotonergic neurotransmission.
    Biochemical Journal 03/2015; DOI:10.1042/BJ20140826
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    ABSTRACT: Mutations in breast cancer susceptibility gene BRCA1 (breast cancer early-onset 1) are associated with increased risk of developing breast and ovarian cancers. BRCA1 is a large protein of 1863 residues with two small structured domains at its termini: a RING domain at the N-terminus and a BRCT (BRCA1 C-terminus domain) repeat domain at the C-terminus. Previously, we quantified the effects of missense mutations on the thermodynamic stability of the BRCT domains, and we showed that many are so destabilizing that the folded functional state is drastically depopulated at physiological temperature. In the present study, we ask whether and how reduced thermodynamic stability of the isolated BRCT mutants translates into loss of function of the full-length protein in the cell. We assessed the effects of missense mutants on different stages of BRCA1-mediated DNA repair by homologous recombination using chicken lymphoblastoid DT40 cells as a model system. We found that all of the mutations, regardless of how profound their destabilizing effects, retained some DNA repair activity and thereby partially rescued the chicken BRCA1 knockout. By contrast, the mutation R1699L, which disrupts the binding of phosphorylated proteins (but which is not destabilizing), was completely inactive. It is likely that both protein context (location of the BRCT domains at the C-terminus of the large BRCA1 protein) and cellular environment (binding partners, molecular chaperones) buffer these destabilizing effects such that at least some mutant protein is able to adopt the folded functional state.
    Biochemical Journal 03/2015; 466(3):613-624. DOI:10.1042/BJ20141077
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    ABSTRACT: Peroxiredoxin-6 (PRDX6) is an unusual member of the peroxiredoxin family of antioxidant enzymes that has only one evolutionarily conserved cysteine. It reduces oxidized lipids and ROS by oxidation of the active site cysteine (Cys-47) to a sulfenic acid, but the mechanism for conversion back to a sulfhydryl is not completely understood. Moreover, it has a phospholipase A2 activity in addition to its peroxidase activity. Interestingly, some biochemical data are inconsistent with a known high-resolution crystal structure of the catalytic intermediate of the protein, and biophysical data indicate the protein undergoes conformational changes that affect enzyme activity. In order to further elucidate the solution structure of this important enzyme, we used chemical cross-linking coupled with high-resolution mass spectrometry (CX-MS), with an emphasis on zero-length cross-links. Distance constraints from high confidence cross-links were used in homology modeling experiments to determine a solution structure of the reduced form of the protein. This structure was further evaluated using chemical cross-links produced by several homo-bifunctional amine-reactive cross-linking reagents, which helped confirm the solution structure. The results show that several regions of the reduced version of human PRDX6 are in a substantially different conformation from that shown for the crystal structure of the peroxidase catalytic intermediate. The differences between these two structures are likely to reflect catalysis-related conformational changes. These studies also demonstrate that CX-MS using zero-length cross-linking is a powerful strategy for probing protein conformational changes that is complementary to alternative methods such as crystallographic, NMR, and biophysical studies.
    Biochemical Journal 03/2015; DOI:10.1042/BJ20141463
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    ABSTRACT: Proteins of the echinoderm microtubule associated protein-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule (MT) network. EML1-4 consist of WD40 repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4-ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding, however this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4-ALK and EML1-ABL1 fusions in which variable portions of the EML component are present. Uniquely, EML4-ALK variant 3, which includes the TD and basic region of EML4 but none of the WD40 repeats, was localized to MTs, both when expressed recombinantly and in a patient-derived NSCLC cell line (H2228). This raises the question of whether the mislocalization of ALK activity to MTs might influence downstream signalling and malignant properties of cells. Furthermore, the structure of EML4 TD may enable the development of protein-protein interaction inhibitors targeting the trimerization interface, providing a possible avenue towards therapeutic intervention in EML4-ALK NSCLC.
    Biochemical Journal 03/2015; DOI:10.1042/BJ20150039
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    ABSTRACT: Metformin is the mainstay therapy for type 2 diabetes (T2D), and many patients also take salicylate-based drugs (i.e. Aspirin; ASA) for cardioprotection. Metformin and salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) and salicylate interacting directly at the AMPK β1 drug binding site. AMPK activation by both drugs results in phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme controlling fatty acid synthesis (lipogenesis). We find doses of metformin and salicylate used clinically synergistically activate AMPK in vitro and in vivo, resulting in reduced liver lipogenesis, lower liver lipid levels and improved insulin sensitivity in mice. Synergism occurs in cell free assays and is specific for the AMPK β1 subunit. These effects are also observed in primary human hepatocytes, and patients with dysglycemia exhibit additional improvements in a marker of insulin resistance (proinsulin) when treated with ASA and metformin compared to either drug alone. These data indicate that metformin-salicylate combination therapy may be efficacious for the treatment of non-alcoholic fatty liver disease and T2D.
    Biochemical Journal 03/2015; DOI:10.1042/BJ20150125
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    ABSTRACT: A monoclonal antibody (mAb) that binds to a transient intermediate may act as a catalyst for the corresponding reaction; here we show this principle can extend on a macro-molecular scale to the induction of mutant-like oligomerisation in a wild-type protein. Using the common, pathogenic Glu342Lys (Z) variant of alpha1-antitrypsin as antigen - whose native state is susceptible to the formation of a proto-oligomeric intermediate - we have produced a mAb (5E3) that increases the rate of oligomerisation of the wild-type (M) variant. Employing ELISA, gel shift, thermal stability and FRET time-course experiments, we show that mAb5E3 does not bind to the native state of alpha1-antitrypsin, but recognises a cryptic epitope in the vicinity of the post-helix A loop and strand 4C that is revealed upon transition to the polymerisation intermediate, and which persists in the ensuing oligomer. This epitope is not shared by loop-inserted monomeric conformations. We show the increased amenity to polymerisation by either the pathogenic Glu342Lys mutation or the binding of mAb5E3 occurs without affecting energetic barrier to polymerisation. As mAb5E3 also does not alter the relative stability of the monomer to intermediate, it acts in a manner similar to the Glu342Lys mutation, by facilitating the conformational interchange between these two states.
    Biochemical Journal 03/2015; DOI:10.1042/BJ20141569
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    ABSTRACT: Histone modification plays important roles in many biological processes such as development and carcinogenesis. Methylation of histone H3 lysine 4 (H3K4) is commonly associated with transcriptional activation of genes. H3K4 methylation in mammalian cells is carried out by COMPASS-like complexes that are composed of catalytic subunits such as MLL1 and multiple regulatory subunits in which WDR5, RBBP5, ASH2, and DPY30 (constituting the WRAD sub-complex) are the major ones shared from yeast to metazoans. We report here a new mode of spatial regulation of H3K4 methyltransferase complexes. PAQR3, a tumor suppressor specifically localized in the Golgi apparatus, negatively regulates H3K4 trimethylation (H3K4me3) in mammalian cells. Consistently, HOXC8 and HOXA9 gene expression was negatively regulated by PAQR3 expression levels. Hypoxia-induced H3K4me3 was augmented by PAQR3 knockdown and suppressed by PAQR3 overexpression in AGS gastric cancer cells. PAQR3 was able to interact directly or indirectly with the four members of the WRAD sub-complex and tether them to the Golgi apparatus, accompanied by reduction of histone methyltransferase activity in the nucleus. PAQR3 also interfered with the interaction of WDR5 with the C-terminus of MLL1. Collectively, our study indicates that PAQR3 negatively modulates H3K4 methylation via altering the subcellular compartmentalization of the core regulatory subunits of the COMPASS-like complexes in mammalian cells.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20141392
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    ABSTRACT: Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2), one of the most abundant circulating IGFBPs, is known to attenuate the biological action of IGF-1. Although the effect of IGFBP-2 in preventing metabolic disorder is well known, its regulatory mechanism remains unclear. Here, we demonstrated the transcriptional regulation of the IGFBP-2 gene by peroxisome proliferator-activated receptor (PPAR) α in the liver. During fasting, both Igfbp-2 and PPARa expression levels were increased. Wy14,643, a selective PPARα agonist, significantly induced IGFBP-2 gene expression in primary cultured hepatocytes. However, IGFBP-2 gene expression in Pparα null mice was not affected by fasting or Wy14,643. In addition, through transient transfection and chromatin immunoprecipitation assay in fasted livers, we determined that PPARα bound to the putative PPAR-response element between -511 bp and ‑499 bp on the IGFBP-2 gene promoter, indicating that the IGFBP-2 gene transcription is activated directly by Pparα. To explore the role of Pparα in IGF-1 signaling, we treated primary cultured hepatocytes with Wy14,643 and observed a decrease in the number of IGF‑1 receptors and in Akt phosphorylation. No inhibition was observed in the hepatocytes isolated from Pparα null mice. These results suggest that PPARα controls IGF-1 signaling through the upregulation of hepatic IGFBP-2 transcription during fasting and Wy14,643 treatment.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20141248
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    ABSTRACT: Constitutive activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over one hundred substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify small molecular weight inhibitors that are intended to target ERK1/2-substrate docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. Here we report the identification and characterization of compounds with a thienyl benzenesulfonate scaffold that were designed to inhibit ERK1/2 substrates containing an F-site or DEF (docking site for ERK, FXF) motif. Experimental evidence shows the compounds inhibit the expression of F-site containing immediate early genes of the Fos family, including c-Fos and Fra1, and transcriptional regulation of the activator protein-1 (AP-1) complex. Moreover, this class of compounds selectively induces apoptosis in melanoma cells containing mutated BRaf and constitutively active ERK1/2 signaling, including melanoma cells that are inherently resistant to clinically relevant kinase inhibitors. These findings represent the identification and initial characterization of a novel class of compounds that inhibit ERK1/2 signaling functions and their potential utility for elucidating ERK1/2 and other signaling events that control the growth and survival of cancer cells containing elevated ERK1/2 activity.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20131571
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    ABSTRACT: Acid ecto-phosphatase activity has been implicated in Leishmania donovani promastigote virulence. Here we report data contributing to the molecular/structural and functional characterization of the Leishmania donovani LdMAcP, member of the histidine acid phosphatase family. LdMAcP, is membrane anchored and shares high sequence identity with the major secreted Leishmania donovani acid phosphatases (LdSAcPs).Sequence comparison of the LdMAcP orthologs in Leishmania spp revealed strain polymorphism and species specificity for the Leishmania donovani complex, responsible for visceral leishmaniasis (Khala azar), proposing thus a potential value of LdMAcP as epidemiological or diagnostic tool. The extracellular orientation of the LdMAcP catalytic domain was confirmed in Leishmania donovani promastigotes, wild type and transgenic overexpressing a recombinant LdMAcP-mRFP1 chimera, as well as in transiently transfected mammalian cells expressing rLdMAcP-His. For the first time it is demonstrated here that LdMAcP confers tartrate resistant acid ecto-phosphatase activity in live Leishmania donovani promastigotes. The latter confirmed the long seeked molecular identity of at least one enzyme contributing to this activity. Interestingly, the Leishmania donovani-rLdMAcP-mRFP1 promastigotes generated in this study, showed significantly higher infectivity and virulence indexes than control parasites in the infection of J774 mouse macrophages highlighting thereby a role for LdMAcP in the parasite's virulence.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20141371
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    ABSTRACT: Decorin binding protein A (DBPA) is an important surface adhesin of the bacterium Borrelia burgdorferi, the causative agent of Lyme disease. DBPA facilitates the bacteria's colonization of human tissue by adhering to glycosaminoglycan (GAG), a sulfated polysaccharide. Interestingly, DBPA sequence variation among different strains of Borrelia spirochetes is high, resulting in significant differences in their GAG affinities. However, the structural mechanisms contributing to these differences are unknown. We determined the solution structures of DBPAs from strain N40 of Borrelia burgdorferi and strain PBr of Borrelia gariini, two DBPA variants whose GAG affinities deviate significantly from strain B31, the most well studied version of DBPA. Our structures revealed that significant differences exist between PBr DBPA and B31/N40 DBPAs. In particular, the C-terminus of PBr DBPA, unlike C-termini from B31 and N40 DBPAs, is positioned away from the GAG-binding pocket, and the linker between helices one and two of PBr DBPA is highly structured and retracted from the GAG-binding pocket. The repositioning of the C-terminus allowed the formation of an extra GAG-binding epitope in PBr DBPA, and the retracted linker give GAG ligands more access to the GAG-binding epitopes than other DBPAs. Characterization of GAG ligands' interactions with wild type PBr and mutants confirmed the importance of the second major GAG-binding epitope and established the fact that the two epitopes are independent of one another and the new epitope is as important to GAG binding as the traditional epitope.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20141201
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    ABSTRACT: Defensins are a class of immune peptides with a broad range of activities against bacterial, fungal, and viral pathogens. Besides exerting direct antimicrobial activity via disorganization of bacterial membranes, defensins are also able to neutralize various unrelated bacterial toxins. Recently we have demonstrated that in the case of human α- and β-defensins this later ability is achieved through exploiting toxins' marginal thermodynamic stability, i.e. defensins act as molecular anti-chaperones unfolding toxin molecules and exposing their hydrophobic regions and thus promoting toxin precipitation and inactivation [Kudryashova, Quintyn, Seveau, Lu, Wysocki, Kudryashov (2014) Immunity 41, 709-721]. Retrocyclins are humanized synthetic θ-defensin peptides that possess unique cyclic structure, differentiating them from α- and β-defensins. Importantly, retrocyclins are more potent against some bacterial and viral pathogens and more stable than their linear counterparts. However, the mechanism of bacterial toxin inactivation by retrocyclins is not known. In the present study we demonstrate that retrocyclins facilitate unfolding of bacterial toxins. Using differential scanning fluorimetry, limited proteolysis, and collisional quenching of internal tryptophan fluorescence, we show that hydrophobic regions of toxins normally buried in the molecule interior become more exposed to solvents and accessible to proteolytic cleavage in the presence of retrocyclins. The retrocyclin-induced unfolding of toxins led to their precipitation and abrogated activity. Toxin inactivation by retrocyclins was strongly diminished under reducing conditions, but preserved at physiological salt and serum concentrations. Therefore, despite significant structural diversity, α-, β-, and θ-defensins employ similar mechanisms of toxin inactivation, which may be shared by antimicrobial peptides from other families.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20150049
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    ABSTRACT: Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical protein kinase which negatively regulates protein synthesis, is activated under stress conditions and plays a role in cytoprotection, e.g., in cancer cells. It is regarded as a possible target for therapeutic intervention in solid tumours. Earlier studies showed that eEF2K is degraded by a proteasome-depended pathway in response to genotoxic stress and that this requires a phosphodegron that includes an autophosphorylation site. Thus, application of eEF2K inhibitors would stabilise eEF2K, partially negating the effects of inhibiting its activity. Here we show that under a range of other stress conditions, including acidosis or treatment of cells with 2-deoxyglucose, eEF2K is also degraded. However, in these settings, the previously-identified phosphodegron is not required for its degradation. Nevertheless, kinase-dead and other activity-deficient mutants of eEF2K are stabilised, as is a mutant lacking a critical autophosphorylation site (Thr348 in eEF2K), which is thought to be required for eEF2K and other a-kinases to achieve their active conformations. In contrast, application of small molecule eEF2K inhibitors does not stabilise the protein. Our data suggest that achieving an active conformation, rather than eEF2K activity per se, are required for its susceptibility to degradation. Additional degrons and E3 ligases beyond those already identified are likely involved in regulating eEF2K levels. Our findings have important implications for therapeutic targeting of eEF2K, e.g., in oncology.
    Biochemical Journal 02/2015; DOI:10.1042/BJ20150089