FEBS Letters RSS feed: Current Issue. FEBS Letters is one of the world's leading journals in biochemistry and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, hypotheses and research letters that merit urgent publication. FEBS Letters offers: • Faster publication: ? Accepted articles are published online in 3 days ? The print version of the article is published in 3 to 5 weeks after acceptance • Full-text article disclosure in HTML and PDF formats • Articles in Press are included in PubMed • Easy online manuscript submission system • Transparent online peer review and manuscript tracking system • No page charges • Free color figures Subject Coverage: The subject area of FEBS Letters is broad. It covers biochemistry (including protein chemistry, enzymology, nucleic acid chemistry, metabolism, and immunochemistry), structural biology, biophysics, computational biology (genomics, proteomics, bioinformatics), molecular genetics, molecular biology and molecular cell biology (signal transduction, intracellular traffic, regulation of cellular proliferation, cell-cell interactions) and systems biology. Studies on microbes, plants and animals at the molecular level are within the scope of FEBS Letters. Submitting Authors: Manuscripts can be submitted to FEBS Letters at: http://ees.elsevier.com/febsletters/ http://www.febsletters.org/?rss=yesElsevier Inc.en © 2012 Federation of European Biochemical Societies. Published by Elsevier Inc. All rights reserved. FEBS Letters0014-579358633 February 2012 © 2012 Federation of European Biochemical Societies. Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.febsletters.org/article/PIIS0014579312000403/abstract?rss=yesEditorial Board10.1016/S0014-5793(12)00040-3FEBS Letters 586, 3 (2012)2012-02-03FEBS Letters2012-02-035863S0014-5793(12)X0003-6iihttp://www.febsletters.org/article/PIIS0014579311009100/abstract?rss=yesHighlights: ► Oryza sativa GUN4, ChlI, ChlD, and ChlH reconstituted Mg-chelatase activity. ► Preactivation of ChlH with GUN4, protoporphyrin and Mg2+ gave maximum activity. ► Protoporphyrin omission during preactivation almost completely abolished activity. ► Protoporphyrin preincubation with OsChlH was most important for preactivation. ► GUN4’s C-terminal is essential for preactivation of ChlH but not porphyrin binding.Abstract: Oryza sativa GUN4 together with the magnesium chelatase subunits ChlI, ChlD, and ChlH have been heterologously expressed and purified to reconstitute magnesium chelatase activity in vitro. Maximum magnesium chelatase activity requires pre-activation of OsChlH with OsGUN4, Mg2+ and protoporphyrin-IX. OsGUN4 and OsChlH preincubated without protoporphyrin-IX yields magnesium chelatase activity similar to assays without OsGUN4, suggesting formation of a dead-end complex. Either 9 or 10 C-terminal amino acids of OsGUN4 are slowly hydrolyzed to yield a truncated OsGUN4. These truncated OsGUN4 still bind protoporphyrin-IX and Mg-protoporphyrin-IX but are unable to activate OsChlH. This suggests the mechanism of GUN4 activation of magnesium chelatase is different in eukaryotes compared to cyanobacteria as the orthologous cyanobacterial GUN4 proteins lack this C-terminal extension.Structured summary of protein interactions: ChlH and ChlH bind by molecular sieving (View interaction)ChlH and ChlH bind by molecular sieving (View interaction)ChlD and ChlD bind by molecular sieving (View interaction)C-terminal residues of Oryza sativa GUN4 are required for the activation of the ChlH subunit of magnesium chelatase in chlorophyll synthesisShuaixiang Zhou, Artur Sawicki, Robert D. Willows, Meizhong Luo10.1016/j.febslet.2011.12.026FEBS Letters 586, 3 (2012)2012-01-03FEBS Letters2012-01-035863S0014-5793(12)X0003-6Research Letters with SDA205210http://www.febsletters.org/article/PIIS0014579311009136/abstract?rss=yesHighlights: ► FLU is part of a protein complex bound to chloroplast membranes, primarily on the thylakoids. ► FLU co-migrates on BNGE with several enzymes of the chlorophyll biosynthesis pathway. ► FLU co-immunoprecipitates with CHL27, POR B, POR C and geranylgeranyl reductase. ► FLU co-immunoprecipitates with GluTR only in the dark.Abstract: Regulation of tetrapyrrole biosynthesis in higher plants has been attributed to negative feedback control. Two effectors of feedback inhibition have been identified, heme and the FLU protein. Inhibition by heme implicates the Fe-branch via regulation of the initial step of tetrapyrrole synthesis. In the present work a FLU-containing chloroplast membrane complex was identified, that besides FLU comprises the four enzymes catalyzing the final steps of chlorophyll synthesis. The results support the notion that FLU links chlorophyll synthesis and the target of feedback control, glutamyl-tRNA reductase, thereby allowing also the Mg-branch to control the initial step of tetrapyrrole synthesis.Structured summary of protein interactions: FLU, CHL27, PORB, PORC and CHLP physically interact by blue native page (View interaction)FLU physically interacts with CHL27, PORB, PORC, CHLP and GluTR by anti tag co-immunoprecipitation (View interaction)FLU physically interacts with CHL27 by anti bait co-immunoprecipitation (View Interaction: 1, 2)FLU physically interacts with CHL27 by anti tag co-immunoprecipitation (View interaction)FLU physically interacts with CHL27, PORB, PORC and CHLP by anti tag co-immunoprecipitation (View interaction)FLU, a negative feedback regulator of tetrapyrrole biosynthesis, is physically linked to the final steps of the Mg++-branch of this pathwayDominika Kauss, Sylvain Bischof, Sandro Steiner, Klaus Apel, Rasa Meskauskiene10.1016/j.febslet.2011.12.029FEBS Letters 586, 3 (2012)2012-01-02FEBS Letters2012-01-025863S0014-5793(12)X0003-6Research Letters with SDA211216http://www.febsletters.org/article/PIIS0014579312000270/abstract?rss=yesHighlights: ► Human airway trypsin-like protease (HAT) cleaves proMSP at the activating site. ► MSP processed by HAT is biologically active. ► HAT silencing in bronchial epithelial cells reduces phosphorylation of MSP receptor.Abstract: Macrophage-stimulating protein (MSP) circulates as a proform protein and requires proteolytic processing for activation. Respiratory ciliated cells express the MSP receptor, recepteur d’origine nantais (RON), at the apical surface, which reportedly has an important role in ciliary function. Like RON, human airway trypsin-like protease (HAT) is also expressed at the apical surface of ciliated cells. Here we show that HAT cleaves proMSP at the physiological activation site, Arg483-Val484. MSP processed by HAT could induce chemotactic responses and morphological changes of peritoneal macrophages. In human respiratory epithelial cells, knock down of HAT expression reduced proMSP processing and RON autophosphorylation. We suggest that HAT is important for MSP-RON signaling in the respiratory tract.Structured summary of protein interactions: HAT cleaves proMSP by protease assay (View interaction)Activation of macrophage-stimulating protein by human airway trypsin-like proteaseHiroshi Orikawa, Makiko Kawaguchi, Takashi Baba, Kenji Yorita, Sumio Sakoda, Hiroaki Kataoka10.1016/j.febslet.2012.01.009FEBS Letters 586, 3 (2012)2012-01-12FEBS Letters2012-01-125863S0014-5793(12)X0003-6Research Letters with SDA217221http://www.febsletters.org/article/PIIS0014579311008799/abstract?rss=yesHighlights: ► Splice blocking of sox31 elicits developmental arrest in zebrafish embryos. ► The Sb MO impairs the zygotic gene “up” and maternal mRNA “down” events during MBT. ► The Sb MO of sox31 induces an apoptotic response.Abstract: Here we report that splice blocking morpholinos (Sb MO) against zebrafish sox31 elicit developmental arrest, likely through creating a series of dominant negative splicing variants. Embryos injected with the Sb MO develop normally before the Mid-Blastula Transition (MBT); however, they do not initiate epiboly. Microarray analysis of mRNAs collected at the dome stage revealed that the Sb MO impairs activation of a large set of zygotic genes and reduces degradation of maternal mRNA during MBT. Furthermore, an apoptotic response occurs in Sb morphants at about 6hpf. SoxB1 family genes including sox31 thus play an essential role for early embryos traversing the transitional stage.Splice blocking of zygotic sox31 leads to developmental arrest shortly after Mid-Blastula Transition and induces apoptosis in zebrafishSheng-Nan Hu, Hui Yu, Yun-Bin Zhang, Zhi-Li Wu, Yuan-Chang Yan, Yi-Xue Li, Yuan-Yuan Li, Yi-Ping Li10.1016/j.febslet.2011.12.008FEBS Letters 586, 3 (2012)2011-12-29FEBS Letters2011-12-295863S0014-5793(12)X0003-6Research Letters222228http://www.febsletters.org/article/PIIS0014579311008830/abstract?rss=yesHighlights: ► Lactoferrin (Lf) inhibits TNF-α-stimulated ICAM-1 expression in endothelial cells. ► Lf down-regulates TNF-α-stimulated ICAM-1 expression at the transcriptional level. ► Lf binds to the proximal NF-κB site in human ICAM-1 promoter in vitro and in vivo. ► Lf interferes with NF-κB for binding to the ICAM-1 promoter region.Abstract: Lactoferrin (Lf) is known to have anti-inflammatory activity, but the mechanisms of action by Lf remain to be elucidated. Here, we demonstrated that TNF-α-induced expression of intercellular adhesion molecule-1 (ICAM-1) was down-regulated by Lf in a DNA-binding dependent manner at transcriptional level in endothelial cells. Our results showed that Lf bound to a DNA region in the ICAM-1 promoter in vitro as well as in chromatin context. Lf inhibited binding of NF-κB to a proximal NF-κB site in ICAM-1 promoter. This type of repression represents an additional mechanism for the action of Lf in regulation of gene expression.Human lactoferrin suppresses TNF-α-induced intercellular adhesion molecule-1 expression via competition with NF-κB in endothelial cellsChan Woo Kim, Tae Hoon Lee, Keun Hyung Park, Sang-Yun Choi, Jiyoung Kim10.1016/j.febslet.2011.12.011FEBS Letters 586, 3 (2012)2012-01-03FEBS Letters2012-01-035863S0014-5793(12)X0003-6Research Letters229234http://www.febsletters.org/article/PIIS001457931100888X/abstract?rss=yesHighlights: ► Generation of non-oxidizable oleate-enriched cardiolipins via mitochondrial targeting. ► Desensitrization to apoptosis via suppression of cardiolipjn oxidation. ► Inhibition of acyl-CoA synthase reinstates polyunsaturation of cardiolipin. ► Inhibition of acyl-CoA synthase reinstates sensitivity to apoptosis.Abstract: Peroxidation of cardiolipin in mitochondria is essential for the execution of apoptosis. We suggested that integration of oleic acid into cardiolipin generates non-oxidizable cardiolipin species hence protects cells against apoptosis. We synthesized mitochondria-targeted triphenylphosphonium oleic acid ester. Using lipidomics analysis we found that pretreatment of mouse embryonic cells with triphenylphosphonium oleic acid ester resulted in decreased contents of polyunsaturated cardiolipins and elevation of its species containing oleic acid residues. This caused suppression of apoptosis induced by actinomycin D. Triacsin C, an inhibitor of acyl-CoA synthase, blocked integration of oleic acid into cardiolipin and restored cell sensitivity to apoptosis.Mitochondria targeting of non-peroxidizable triphenylphosphonium conjugated oleic acid protects mouse embryonic cells against apoptosis: Role of cardiolipin remodelingYulia Y. Tyurina, Muhammad A. Tungekar, Mi-Yeon Jung, Vladimir A. Tyurin, Joel S. Greenberger, Detcho A. Stoyanovsky, Valerian E. Kagan10.1016/j.febslet.2011.12.016FEBS Letters 586, 3 (2012)2011-12-29FEBS Letters2011-12-295863S0014-5793(12)X0003-6Research Letters235241http://www.febsletters.org/article/PIIS0014579311009094/abstract?rss=yesHighlights: ► Kinetic evaluation of chAPE1 metal ion specificity. ► Use of inhibitory and activating metal ion to probe for the catalytic mechanism. ► Two metal ion assisted catalysis describes best the mechanism of chAPE1. ► Crystal structures depict non-productive metal ion complexes with substrates and products.Abstract: The APE1, an important mammalian AP endonuclease, is an essential enzyme in the base excision DNA repair pathway (BER). The number of metal ions involved directly in the catalysis remains controversial. Here we describe the metal ion titration experiments that demonstrate the requirement for two metal ions for the endonuclease activity of the Chinese hamster APE1. The titration with the non-activating metal ion La3+ showed a biphasic behavior with activating and inhibitory effects of La3+ in the range of 0–100μM in the presence of 5mMMg2+. Modeling of the enzyme-substrate/product complexes provided insight into the endonuclease activity and elucidated the nature of the crystal structures. Accordingly, we proposed a reaction scheme for the two-metal ion assisted catalysis of chAPE1 endonuclease activity.Chinese hamster AP endonuclease operates by a two-metal ion assisted catalytic mechanismMandula Borjigin, Pablo Arenaz, Boguslaw Stec10.1016/j.febslet.2011.12.025FEBS Letters 586, 3 (2012)2011-12-29FEBS Letters2011-12-295863S0014-5793(12)X0003-6Research Letters242247http://www.febsletters.org/article/PIIS0014579311009112/abstract?rss=yesHighlights: ► SGLT are sodium-dependent sugar cotransporters. ► We cloned and functionally characterised a new family member SGLT5. ► We identified SGLT5 as a kidney specific mannose transporter.Abstract: Sodium glucose cotransporters (SGLT) actively catalyse carbohydrate transport across cellular membranes. Six of the 12 known SGLT family members have the capacity to bind and/or transport monosaccharides (SGLT-1 to 6); of these, all but SGLT-5 have been characterised. Here we demonstrate that human SGLT-5 is exclusively expressed in the kidney. Four splice variants were detected and the most abundant SGLT-5-mRNA was functionally characterised. SGLT-5 mediates sodium-dependent [14C]-α-methyl-d-glucose (AMG) transport that can be inhibited by mannose, fructose, glucose, and galactose. Uptake studies using demonstrated high capacity transport for mannose and fructose and, to a lesser extent, glucose, AMG, and galactose. SGLT-5 mediated mannose, fructose and AMG transport was weakly (μM potency) inhibited by SGLT-2 inhibitors. In summary, we have characterised SGLT-5 as a kidney mannose transporter. Further studies are warranted to explore the physiological role of SGLT-5.Functional characterisation of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporterRolf Grempler, Robert Augustin, Stefanie Froehner, Tobias Hildebrandt, Eric Simon, Michael Mark, Peter Eickelmann10.1016/j.febslet.2011.12.027FEBS Letters 586, 3 (2012)2012-01-02FEBS Letters2012-01-025863S0014-5793(12)X0003-6Research Letters248253http://www.febsletters.org/article/PIIS0014579311009124/abstract?rss=yesHighlights: ► T82M mutation does not change contacts with UDPG and Tyr194 positioning. ► Autoglucosylation, DBM glucosylation and UDPG hydrolysis are abolished in T82M mutant. ► Glucose transfer activities are lost by Val but not by Ser substitution of Thr82.Abstract: The X-ray structure of rabbit glycogenin containing the T82M (T83M according to previous authors amino acid numbering ) mutation causing glycogenosis showed the loss of Thr82 hydrogen bond to Asp162, the residue involved in the activation step of the glucose transfer reaction mechanism. Autoglucosylation, maltoside transglucosylation and UDP-glucose hydrolyzing activities were abolished even though affinity and interactions with UDP-glucose and positioning of Tyr194 acceptor were conserved. Substitution of Thr82 for serine but not for valine restored the maximum extent of autoglucosylation as well as transglucosylation and UDP-glucose hydrolysis rate. Results provided evidence sustaining the essential role of the lost single hydrogen bond for UDP-glucose activation leading to glycogenin-bound glycogen primer synthesis.Structural and biochemical insight into glycogenin inactivation by the glycogenosis-causing T82M mutationMaría E. Carrizo, Jorge M. Romero, Federico M. Issoglio, Juan A. Curtino10.1016/j.febslet.2011.12.028FEBS Letters 586, 3 (2012)2012-01-04FEBS Letters2012-01-045863S0014-5793(12)X0003-6Research Letters254257http://www.febsletters.org/article/PIIS0014579311009161/abstract?rss=yesHighlights: ► Transcription factor CI changes its structure upon DNA-binding. ► Differential protein dynamics upon binding with different DNA sequences. ► Exploration of dynamical time scale associated with the protein–DNA interaction. ► Structural aspects of DNA-bound CI–CI co-operative interactions are investigated.Abstract: λ-Repressor–operator sites interaction, particularly OR1 and OR2, is a key component of the λ-genetic switch. FRET from the dansyl bound to the C-terminal domain of the protein, to the intercalated EtBr in the operator DNA indicates that the structure of the protein is more compact in the OR2 complex than in the OR1 complex. Fluorescence anisotropy reveals enhanced flexibility of the C-terminal domain of the repressor at fast timescales after complex formation with OR1. In contrast, OR2 bound repressor shows no significant enhancement of protein dynamics at these timescales. These differences are shown to be important for correct protein–protein interactions. Altered protein dynamics upon specific DNA sequence recognition may play important roles in assembly of regulatory proteins at the correct positions.Recognition of different DNA sequences by a DNA-binding protein alters protein dynamics differentiallyTanumoy Mondol, Subrata Batabyal, Abhishek Mazumder, Siddhartha Roy, Samir Kumar Pal10.1016/j.febslet.2011.12.032FEBS Letters 586, 3 (2012)2012-01-09FEBS Letters2012-01-095863S0014-5793(12)X0003-6Research Letters258262http://www.febsletters.org/article/PIIS0014579312000154/abstract?rss=yesHighlights: ► We investigate the role of VapB in RANKL-induced osteoclast differentiation. ► Knock-down of VapB suppressed osteoclastogenesis. ► Over-expression of VapB accelerated RANKL-mediated osteoclast differentiation by induction of NFATc1. ► VapB regulates RANKL-mediated osteoclastogenesis via PLCγ2-Ca2+-NFAT signaling.Abstract: VapB has been shown to regulate calcium homeostasis in amyotrophic lateral sclerosis. Calcium signaling is also important in metabolic bone diseases, but the role of VapB in the generation of osteoclasts for bone resorption during osteoclastogenesis is not known. Therefore, we investigated the role of VapB in RANKL-induced osteoclast differentiation. Interestingly, VapB is induced during osteoclastogenesis, and regulates osteoclast differentiation by modulating NFATc1. The results also suggest that VapB regulates osteoclastogenesis via PLCγ2-Ca2+-NFAT signaling. The involvement of PLCγ2-Ca2+-NFAT signaling in VapB-regulated osteoclastogenesis was confirmed by a pharmacological study. Taken together, the results indicate that VapB positively regulates RANKL-mediated osteoclastogenesis via PLCγ2-Ca2+-NFAT signaling.VapB as a regulator of osteoclastogenesis via modulation of PLCγ2-Ca2+-NFAT signalingSik-Won Choi, Jeong-Tae Yeon, Kie-In Park, Chang Hoon Lee, Byung Soo Youn, Jaemin Oh, Myeung Su Lee10.1016/j.febslet.2011.12.033FEBS Letters 586, 3 (2012)2012-01-11FEBS Letters2012-01-115863S0014-5793(12)X0003-6Research Letters263269http://www.febsletters.org/article/PIIS0014579312000178/abstract?rss=yesHighlights: ► Yeast as a model system for drug mechanism of action. ► Mechanism for anti-diabetic and anti-obesity agent sodium tungstate. ► Tungstate modulates yeast translational control (GCN) pathway. ► Tungstate inhibits GCN negative regulator Glc7p phosphatase. ► Tungstate as a putative therapy on GCN-related diseases.Abstract: Tungstate counteracts diabetes and obesity in animal models, but its molecular mechanisms remain elusive. Our Saccharomyces cerevisiae-based approach has found that tungstate alleviated the growth defect induced by nutrient stress and enhanced the activation of the GCN pathway. Tungstate relieved the sensitivity to starvation of a gcn2-507 yeast hypomorphic mutant, indicating that tungstate modulated the GCN pathway downstream of Gcn2p. Interestingly, tungstate inhibited Glc7p and PP1 phosphatase activity, both negative regulators of the GCN pathway in yeast and humans, respectively. Accordingly, overexpression of a dominant-negative Glc7p mutant in yeast mimicked tungstate effects. Therefore tungstate alleviates nutrient stress in yeast by in vivo inhibition of Glc7p. These data uncover a potential role for tungstate in the treatment of PP1 and GCN related diseases.Anti-diabetic and anti-obesity agent sodium tungstate enhances GCN pathway activation through Glc7p inhibitionC.J. Rodriguez-Hernandez, J.J. Guinovart, J.R. Murguia10.1016/j.febslet.2011.12.035FEBS Letters 586, 3 (2012)2012-01-11FEBS Letters2012-01-115863S0014-5793(12)X0003-6Research Letters270276http://www.febsletters.org/article/PIIS001457931200018X/abstract?rss=yesHighlights: ► Hemagglutinin of influenza virus associates with rafts of the plasma membrane. ► A raft-targeting signal in the outer part of the transmembrane region was mutated. ► Processing of HA and co-localization with a Golgi-marker was analyzed. ► Transport through the Golgi, but not trimerization in the ER, was retarded. ► The second signal for raft-targeting, S-acylation, had no effect on transport.Abstract: Inclusion of proteins into membrane-rafts favours interactions required for virus assembly but has also been proposed to facilitate vesicular transport of proteins. The hemagglutinin (HA) of influenza virus contains a raft-targeting sequence in the outer leaflet of its transmembrane region. We report that its mutation enhances co-localization of HA with a cis-Golgi marker and retards Golgi-localized processing, such as acquisition of Endo-H resistant carbohydrates and proteolytic cleavage. In contrast, trimerization of the molecule in the ER and transport to the apical membrane were not affected. The second signal for raft-targeting, S-acylation at cytoplasmic cysteines, did not retard HA transport.Mutation of a raft-targeting signal in the transmembrane region retards transport of influenza virus hemagglutinin through the GolgiStephanie Engel, Maren de Vries, Andreas Herrmann, Michael Veit10.1016/j.febslet.2012.01.002FEBS Letters 586, 3 (2012)2012-01-11FEBS Letters2012-01-115863S0014-5793(12)X0003-6Research Letters277282http://www.febsletters.org/article/PIIS0014579312000208/abstract?rss=yesHighlights: ► Starter C domain of non-ribosomal peptide synthetases. ► Lipoinitiation reaction of CDA. ► Substrate specificity of the starter C domain Cda-C1. ► In vitro studies of N-acylation of PCP-bound serine.Abstract: The non-ribosomally synthesized lipodepsipeptide CDA belongs to the group of acidic lipopeptide antibiotics, whose members feature a fatty acid side chain that strongly affects their antimicrobial activity. This study elucidates the N-acylation of the N-terminal serine in the CDA peptide chain. This reaction is referred to as lipoinitiation and is shown to be catalyzed by the dissected starter C domain found at the N-terminus of Cda-PSI. The recombinantly produced C domain specifically interacts with 2,3-epoxyhexanoyl-S-ACP and catalyzes the transfer of the fatty acid moiety onto the amino group of PCP-bound serine with high selectivity for both carrier protein bound substrates at the donor and acceptor site.Exploring the mechanism of lipid transfer during biosynthesis of the acidic lipopeptide antibiotic CDAFemke I. Kraas, Tobias W. Giessen, Mohamed A. Marahiel10.1016/j.febslet.2012.01.003FEBS Letters 586, 3 (2012)2012-01-11FEBS Letters2012-01-115863S0014-5793(12)X0003-6Research Letters283288