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1.	Na Zhao, Li, et al. (författare) Cascading proton transfers are a hallmark of the catalytic mechanism of SAM-dependent methyltransferases 2020 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 594:13, s. 2128-2139 Tidskriftsartikel (refereegranskat)abstract The S-adenosyl-L-methionine (SAM)-dependent methyltransferases attach a methyl group to the deprotonated methyl lysine (Kme0) using SAM as a donor. An intriguing, yet unanswered, question is how the deprotonation of the methyl lysine takes place which results in a lone pair of electrons at the Nϵ atom of the methyl lysine for the following methyl transfer. PRDM9, one of the few methyltransferases with well-defined enzyme activity in vitro and in vivo, is a good representative of the PR/SET domain methyltransferase family to study the deprotonation and subsequently the methyl transfer. The reaction consists of two progressing steps: (i) the absolutely required substrate methyl lysine deprotonation and (ii) the transfer of the methyl group to the deprontonated methyl lysine. We use empirical valence bond (EVB) simulations to evaluate Y357 at the active site as potential general base for the deprotonation of the methyl lysine. Indeed, our study has found that the pKa of Tyr357 is low enough to make it an ideal candidate for proton abstraction from the methyl lysine. The partially deprontonated Tyr357 is able to change its H-bond pattern thus bridging two proton tunneling states (OH- H 0-Tyr357 and Kme0-Nϵ H O-Tyr357) and providing a cascading proton transfer from Tyr357 to hydroxide, generating deprotonated Tyr357 and then from Kme0 to the deprotonated Tyr357 resulting in deprotonated methyl lysine. This cascading proton transfer shortens the lifespan of the labile intermediates, and affects the conformational changes during the product release important to promote the proton release to the bulk solvent. Our computational efforts have uncovered a new catalytic mechanism to unravel the unanswered question about the deprotonation of the methyl lysine in methyltransferases.
2.	Riesbeck, Kristian (författare) Complement evasion by the human respiratory tract pathogens Haemophilus influenzae and Moraxella catarrhalis 2020 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 594:16, s. 2586-2597 Forskningsöversikt (refereegranskat)abstract All infective bacterial species need to conquer the innate immune system in order to colonize and survive in their hosts. The human respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis are no exceptions and have developed sophisticated mechanisms to evade complement-mediated killing. Both bacterial species carry lipooligosaccharides preventing complement attacks and attract and utilize host complement regulators C4b binding protein and factor H to inhibit the classical and alternative pathways of complement activation, respectively. In addition, the regulator of the terminal pathway of complement activation, vitronectin, is hijacked by both bacteria. An array of different outer membrane proteins (OMP) in H. influenzae and M. catarrhalis simultaneously binds complement regulators, but also plasminogen. Several of the bacterial complement-binding proteins are important adhesins and contain highly conserved regions for interactions with the host. Thus, some of the OMP are viable targets for new therapeutics, including vaccines aimed at preventing respiratory tract diseases such as otitis media in children and exacerbations in patients suffering from chronic obstructive pulmonary disease.
3.	Ahmadpour, Doryaneh, 1973, et al. (författare) The mitogen-activated protein kinase Slt2 modulates arsenite transport through the aquaglyceroporin Fps1 2016 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 590:20, s. 3649-3659 Tidskriftsartikel (refereegranskat)abstract © 2016 Federation of European Biochemical Societies Arsenite is widely present in nature; therefore, cells have evolved mechanisms to prevent arsenite influx and promote efflux. In yeast (Saccharomyces cerevisiae), the aquaglyceroporin Fps1 mediates arsenite influx and efflux. The mitogen-activated protein kinase (MAPK) Hog1 has previously been shown to restrict arsenite influx through Fps1. In this study, we show that another MAPK, Slt2, is transiently phosphorylated in response to arsenite influx. Our findings indicate that the protein kinase activity of Slt2 is required for its role in arsenite tolerance. While Hog1 prevents arsenite influx via phosphorylation of T231 at the N-terminal domain of Fps1, Slt2 promotes arsenite efflux through phosphorylation of S537 at the C terminus. Our data suggest that Slt2 physically interacts with Fps1 and that this interaction depends on phosphorylation of S537. We hypothesize that Hog1 and Slt2 may affect each other's binding to Fps1, thereby controlling the opening and closing of the channel.
4.	Birtele, Marcella, et al. (författare) Dual modulation of neuron-specific microRNAs and the REST complex promotes functional maturation of human adult induced neurons 2019 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:23, s. 3370-3380 Tidskriftsartikel (refereegranskat)abstract Direct neuronal reprogramming can be achieved using different approaches: by expressing neuronal transcription factors or microRNAs; and by knocking down neuronal repressive elements. However, there still exists a high variability in terms of the quality and maturity of the induced neurons obtained, depending on the reprogramming strategy employed. Here, we evaluate different long-term culture conditions and study the effect of expressing the neuronal-specific microRNAs, miR124 and miR9/9*, while reprogramming with forced expression of the transcription factors Ascl1, Brn2, and knockdown of the neuronal repressor REST. We show that the addition of microRNAs supports neuronal maturation in terms of gene and protein expression, as well as in terms of electrophysiological properties.
5.	Daniel, Michael G., et al. (författare) Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture 2019 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:23, s. 3266-3287 Tidskriftsartikel (refereegranskat)abstract Transcription factor (TF)-based reprogramming of somatic tissues holds great promise for regenerative medicine. Previously, we demonstrated that the TFs GATA2, GFI1B, and FOS convert mouse and human fibroblasts to hemogenic endothelial-like precursors that generate hematopoietic stem progenitor (HSPC)-like cells over time. This conversion is lacking in robustness both in yield and biological function. Herein, we show that inclusion of GFI1 to the reprogramming cocktail significantly expands the HSPC-like population. AFT024 coculture imparts functional potential to these cells and allows quantification of stem cell frequency. Altogether, we demonstrate an improved human hemogenic induction protocol that could provide a valuable human in vitro model of hematopoiesis for disease modeling and a platform for cell-based therapeutics. Database: Gene expression data are available in the Gene Expression Omnibus (GEO) database under the accession number GSE130361.
6.	Kelley, Liam P., et al. (författare) Dimerization of small integral membrane protein 1 promotes cell surface presentation of the Vel blood group epitope 2020 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 594:8, s. 1261-1270 Tidskriftsartikel (refereegranskat)abstract The Vel blood group antigen is carried on the short extracellular segment of the 78-amino-acid-long, type II transmembrane protein SMIM1 of unknown function. Here, using biochemical analysis and flow cytometry of cells expressing wild-type and mutant alleles of SMIM1, we demonstrate that dimerization of SMIM1 promotes cell surface display of the Vel epitope. We show that SMIM1 dimerization is mediated both by an extracellular Cys77-dependent, homomeric disulfide linkage and via a GxxxG helix–helix interaction motif in the transmembrane domain. These results provide important context for the observed variability in reactivity patterns of clinically important anti-Vel identified in patient sera.
7.	Klaubauf, Sylvia, 1981, et al. (författare) A novel L-arabinose-responsive regulator discovered in the rice-blast fungus Pyricularia oryzae (Magnaporthe oryzae) 2016 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 590:4, s. 550-558 Tidskriftsartikel (refereegranskat)abstract In this study we identified the L-arabinose-responsive regulator of Pyricularia oryzae that regulates L-arabinose release and catabolism. Previously we identified the Zn2Cys6 transcription factor (TF), AraR, that has this role in the Trichocomaceae family (Eurotiales), but is absent in other fungi. Candidate Zn2Cys6 TF genes were selected according to their transcript profiles on L-arabinose. Deletion mutants of these genes were screened for their growth phenotype on L-arabinose. One mutant, named Delta ara1, was further analyzed. Our analysis demonstrated that Ara1 from P. oryzae is the functional analog of AraR from A. niger, while there is no significant sequence similarity between them.
8.	Košenina, Sara, et al. (författare) Crystal structure of the catalytic domain of the Weissella oryzae botulinum-like toxin 2019 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:12, s. 1403-1410 Tidskriftsartikel (refereegranskat)abstract Botulinum neurotoxins (BoNTs) are the most potent toxins known. So far, eight serotypes have been identified that all act as zinc-dependent endopeptidases targeting SNARE proteins and inhibiting the release of neurotransmitters. Recently, the first botulinum toxin-like protein was identified outside the Clostridial genus, designated BoNT/Wo in the genome of Weissella oryzae. Here, we report the 1.6 angstrom X-ray crystal structure of the light chain of BoNT/Wo (LC/Wo). LC/Wo presents the core fold common to BoNTs but has an unusually wide, open and negatively charged catalytic pocket, with an additional Ca2+ ion besides the zinc ion and a unique ss-hairpin motif. The structural information will help establish the substrate profile of BoNT/Wo and help our understanding of how BoNT evolved.
9.	Palmer, Nathan, et al. (författare) Diverse roles for CDK-associated activity during spermatogenesis 2019 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 593:20, s. 2925-2949 Forskningsöversikt (refereegranskat)abstract The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners, is to promote mitotic division in somatic cells. This canonical cell cycle-associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly several CDKs exhibit meiosis-specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis-specific functions are mediated by both known CDK/cyclin complexes and meiosis-specific CDK-regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.
10.	Scaletti, Emma, et al. (författare) Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs 2019 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:14, s. 1863-1873 Tidskriftsartikel (refereegranskat)abstract Serine hydroxymethyltransferase (SHMT) is the major source of 1-carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms, which are upregulated in numerous cancers, making the enzyme an attractive drug target. Here, we show that the antifolates lometrexol and pemetrexed are inhibitors of SHMT2 and solve the first SHMT2-antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 indicates a highly conserved active site architecture. This structural information offers insights as to how these compounds could be improved to produce more potent and specific inhibitors of this emerging anti-cancer drug target.
11.	Škerlová, Jana, et al. (författare) Structure and steroid isomerase activity of Drosophila glutathione transferase E14 essential for ecdysteroid biosynthesis 2020 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 594:7, s. 1187-1195 Tidskriftsartikel (refereegranskat)abstract Ecdysteroids are critically important for the formation of the insect exoskeleton. Cholesterol is a precursor of ecdysone and its active form 20-hydroxyecdysone, but some steps in the ecdysteroid biosynthesis pathway remain unknown. An essential requirement of glutathione (GSH) transferase GSTE14 in ecdysteroid biosynthesis has been established in Drosophila melanogaster, but its function is entirely unknown. Here, we have determined the crystal structure of GSTE14 in complex with GSH and investigated the kinetic properties of GSTE14 with alternative substrates. GSTE14 has high-ranking steroid double-bond isomerase activity, albeit 50-fold lower than the most efficient mammalian GSTs. Corresponding steroid isomerizations are unknown in insects, and their exact physiological role remains to be shown. Nonetheless, the essential enzyme GSTE14 is here demonstrated to be catalytically competent and have a steroid-binding site.
12.	Arnling Bååth, Jenny, 1987, et al. (författare) A glucuronoyl esterase from Acremonium alcalophilum cleaves native lignin-carbohydrate ester bonds 2016 Ingår i: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 590:16, s. 2611-2618 Tidskriftsartikel (refereegranskat)abstract The Glucuronoyl esterases (GE) have been proposed to target lignin-carbohydrate (LC) ester bonds between lignin moieties and glucuronic acid side groups of xylan, but to date, no direct observations of enzymatic cleavage on native LC ester bonds have been demonstrated. In the present investigation, LCC fractions from spruce and birch were treated with a recombinantly produced GE originating from Acremonium alcalophilum (AaGE1). A combination of size exclusion chromatography and 31P NMR analyses of phosphitylated LCC samples, before and after AaGE1 treatment provided the first evidence for cleavage of the LC ester linkages existing in wood.
13.	Aevarsson, A, et al. (författare) Ligands to the 2Fe iron-sulfur center in succinate dehydrogenase 1988 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 232:2, s. 298-302 Tidskriftsartikel (refereegranskat)abstract Membrane-bound succinate oxidoreductases are flavoenzymes containing one each of a 2Fe, a 3Fe and a 4Fe iron-sulfur center. Amino acid sequence homologies indicate that all three centers are located in the Ip (B) subunit. From polypeptide and gene analysis of Bacillus subtillis succinate dehydrogenase-defective mutants combined with earlier EPR spectroscopic data, we show that four conserved cysteine residues in the first half of Ip are the ligands to the [2Fe-2S] center. These four residues have previously been predicted to be the ligands. Our results also suggest that the N-terminal part of B. subtilis Ip constitutes a domain which can incorporate separately the 2Fe center and interact with Fp, the flavin-containing subunit of the dehydrogenase.
14.	Eriksson, Svante, 1957, et al. (författare) INTERACTION OF BENZ A PYRENE DIOL EPOXIDE WITH CHROMATIN STUDIED BY FLOW LINEAR DICHROISM 1989 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 248:1-2, s. 201-204 Tidskriftsartikel (refereegranskat)
15.	Hagmar, Per, et al. (författare) UNSPECIFIC DNA-BINDING OF THE DNA-BINDING DOMAIN OF THE GLUCOCORTICOID RECEPTOR STUDIED WITH FLOW LINEAR DICHROISM 1989 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 253:1-2, s. 28-32 Tidskriftsartikel (refereegranskat)
16.	Hägerhäll, Cecilia, et al. (författare) A structural model for the membrane-integral domain of succinate:quinone oxidoreductases 1996 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. Tidskriftsartikel (refereegranskat)abstract Many succinate:quinone oxidoreductases in bacteria and mitochondria, i.e, succinate:quinone reductases and fumarate reductases, contain in the membrane anchor a cytochrome b whose structure and function is poorly understood, Based on biochemical data and polypeptide sequence information, we show that the anchors in different organisms are related despite an apparent diversity in polypeptide and heme composition, A general structural model for the membrane-integral domain of the anchors is proposed, It is an antiparallel four-helix bundle with a novel arrangement of hexa-coordinated protoheme M. The structure can be applied to a larger group of membrane-integral cytochromes of b-type and has evolutionary and functional implications.
17.	Kim, Seog K., et al. (författare) METHYL GREEN - A DNA MAJOR-GROOVE BINDING-DRUG 1993 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 315:1, s. 61-64 Tidskriftsartikel (refereegranskat)abstract Interaction and binding geometries of complexes of Methyl green with poly(dA-dT)2, poly(dA) . poly(dT), and triplex poly(dA) . 2poly(dT) complexes have been studied by linear dichroism. For both of the complexes with double helical DNAs, the z symmetry axis of Methyl green is found to be approximately parallel to the DNA bases while the x symmetry axis lies at 40-44-degrees relative to the local DNA helix axis, in agreement with a groove binding mode. However, in contrast to minor-groove binders (such as DAPI and Hoechst 33258) Methyl green is found to be excluded from binding to the triple helical poly(dA) . 2poly(dT) in which the major groove is filled by the third strand. While most so far studied groove-binding dyes bind in the minor groove of DNA, Methyl green thus appears to be an exception.
18.	Larsson, Christer, et al. (författare) Sidedness of plant plasma membrane vesicles purified by partitioning in aqueous two-phase systems 1984 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 171:2, s. 271-276 Tidskriftsartikel (refereegranskat)
19.	Maguire, John J., et al. (författare) EPR characterization of soluble fragments of succinate dehydrogenase from mutant strains of Bacillus subtilis 1989 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 256:1-2, s. 195-199 Tidskriftsartikel (refereegranskat)
20.	Nordén, Bengt, 1945, et al. (författare) Binding of inert metal complexes to deoxyribonucleic acid detected by linear dichroism 1976 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 67:3, s. 368-370 Tidskriftsartikel (refereegranskat)
21.	Nordén, Bengt, 1945 (författare) Rearrangement of a platinum (II) complex in DNA from intercalation outer-sphere position to non-intercalation coordination 1978 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 94:2, s. 204-206 Tidskriftsartikel (refereegranskat)
22.	Rahn, Tova, et al. (författare) Essential role of phosphatidylinositol 3-kinase in insulin-induced activation and phosphorylation of the cGMP-inhibited cAMP phosphodiesterase in rat adipocytes. Studies using the selective inhibitor wortmannin 1994 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 350:2-3, s. 314-318 Tidskriftsartikel (refereegranskat)abstract Incubation of rat adipocytes with wortmannin, a potent and selective phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, completely blocked the antilipolytic action of insulin (IC50 = 100 nM), the insulin-induced activation and phosphorylation of cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) as well as the activation of the insulin-stimulated cGI-PDE kinase (IC50 = 10-30 nM). No direct effects of the inhibitor on the insulin-stimulated cGI-PDE kinase, the cGI-PDE and the hormone-sensitive lipase were observed. These data suggest that activation of PI 3-kinase upstream of the insulin-stimulated cGI-PDE kinase in the antilipolytic insulin signalchain has an essential role for insulin-induced cGI-PDE activation/phosphorylation and anti-lipolysis.
23.	Smirnova, Irina A., et al. (författare) HOQNO interaction with cytochrome b in succinate:menaquinone reductase from Bacillus subtilis 1995 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 359:1, s. 23-26 Tidskriftsartikel (refereegranskat)abstract 2-n-Heptyl4-hydroxyquinoline-N-oxide (HOQNO) inhibits the succinate:quinone oxidoreductase activity of isolated and membrane-bound succinate:menaquinone oxidoreductase of B. subtilis. The inhibition pattern resembles closely that observed for α-thenoyltrifluoroacetone and carboxins in the mitochondrial succinate:ubiquinone oxidoreductase: ca. 90% of the activity is highly sensitive to HOQNO (K i ca. 0.2 μM for the isolated enzyme) whereas the rest 10% proves to be resistant to the inhibitor. HOQNO binding is shown to perturb the absorption spectrum of the ferrous di-heme cytochrome b of the B. subtilis succinate:quinone oxidoreductase both in the α and Soret bands. In addition, the inhibitor is shown to bring about a negative shift of E m of the low-potential heme b. It is suggested that HOQNO interacts with a menasemiquinone binding site near the low-potential heme and suppresses the MQ.−-to-MQH2 step of the quinone reductase reaction but allows partly for the MQ-to-MQ.− transition to occur; dismutation of MQ. formed in the latter reaction to MQ and MQH2 may account for the 10% of the enzyme activity insensitive to HOQNO.
24.	Sundler, Roger, et al. (författare) Quantitative role of base exchange in phosphatidylethanolamine synthesis in isolated hepatocytes. 1974 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 43:3, s. 303-307 Tidskriftsartikel (refereegranskat)
25.	Takahashi, Masayuki, 1949, et al. (författare) STRUCTURE OF UVRABC EXCINUCLEASE UV-DAMAGED DNA COMPLEXES STUDIED BY FLOW LINEAR DICHROISM - DNA CURVED BY UVRB AND UVRC 1992 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 314:1, s. 10-12 Tidskriftsartikel (refereegranskat)abstract The interaction between UvrABC excinuclease from Escherichia coli and ultraviolet light- (UV) damaged DNA was studied by flow linear dichroism. The dichroism signal from DNA was drastically decreased in intensity upon incubation with UvrA and UvrB or whole enzyme in the presence of effector ATP. The change was specific for UV-damaged DNA, and a concluded suppressed DNA orientation suggests the wrapping of DNA around the protein. The incubation with the UvrC subunit alone also somewhat reduces the signal, however, in this case the change was smaller and not specific for UV-damaged DNA. The structural modification of DNA, promoted by the (UvrA2-UvrB) complex, probably facilitates or stabilizes the interaction of the UvrC subunit with DNA for the excision.
26.	Krishnaswamyreddy, Sumitha, et al. (författare) A β-mannan utilisation locus in Bacteroides ovatus involves a GH36 α-galactosidase active on galactomannans 2016 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 590:14, s. 2106-2118 Tidskriftsartikel (refereegranskat)abstract The Bacova_02091 gene in the β-mannan utilisation locus of Bacteroides ovatus encodes a family GH36 α-galactosidase (BoGal36A), transcriptionally upregulated during growth on galactomannan. Characterisation of recombinant BoGal36A reveals unique properties compared to other GH36 α-galactosidases, which preferentially hydrolyse terminal α-galactose in raffinose family oligosaccharides. BoGal36A prefers hydrolysing internal galactose substitutions from intact and depolymerized galactomannan. BoGal36A efficiently releases (>90%) galactose from guar and locust bean galactomannans, resulting in precipitation of the polysaccharides. As compared to other GH36 structures, the BoGal36A 3D model displays a loop deletion, resulting in a wider active site cleft which likely can accommodate a galactose-substituted polymannose backbone. This article is protected by copyright. All rights reserved.
27.	Kumar, Pravin, et al. (författare) Clinically observed deletions in SARS-CoV-2 Nsp1 affect its stability and ability to inhibit translation 2022 Ingår i: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 596:9, s. 1203-1213 Tidskriftsartikel (refereegranskat)abstract Nonstructural protein 1 (Nsp1) of SARS-CoV-2 inhibits host cell translation through an interaction between its C-terminal domain and the 40S ribosome. The N-terminal domain (NTD) of Nsp1 is a target of recurring deletions, some of which are associated with altered COVID-19 disease progression. Here, we characterize the efficiency of translational inhibition by clinically observed Nsp1 deletion variants. We show that a frequent deletion of residues 79–89 severely reduces the ability of Nsp1 to inhibit translation while not abrogating Nsp1 binding to the 40S. Notably, while the SARS-CoV-2 5′ untranslated region enhances translation of mRNA, it does not protect from Nsp1-mediated inhibition. Finally, thermal stability measurements and structure predictions reveal a correlation between stability of the NTD and the efficiency of translation inhibition.
28.	Petrlova, Jitka, et al. (författare) SARS-CoV-2 spike protein aggregation is triggered by bacterial lipopolysaccharide 2022 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 596:19, s. 2566-2575 Tidskriftsartikel (refereegranskat)abstract SARS-CoV-2 spike (S) protein is crucial for virus invasion in COVID-19. Here, we showed that lipopolysaccharide (LPS) can trigger S protein aggregation at high doses of LPS and S protein. We demonstrated the formation of S protein aggregates by microscopy analyses, aggregation and gel shift assays. LPS at high levels boosts the formation of S protein aggregates as detected by amytracker and thioflavin T dyes that specifically bind to aggregating proteins. We validated the role of LPS by blocking the formation of aggregates by the endotoxin-scavenging thrombin-derived peptide TCP-25. Aggregation-prone sequences in S protein are predicted to be nearby LPS binding sites, while molecular simulations showed stable formation of S protein–LPS higher-order oligomers. Collectively, our results provide evidence of LPS-induced S protein aggregation.
29.	Uzuncayir, Sibel, et al. (författare) Analyses of the complex formation of staphylococcal enterotoxin A and the human gp130 cytokine receptor 2022 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 596:7, s. 910-923 Tidskriftsartikel (refereegranskat)abstract Superantigens (SAgs) are bacterial enterotoxins produced by Staphylococcus aureus. Staphylococcal enterotoxin type A (SEA), a staphylococcal superantigen, has been shown to bind to the cytokine signalling receptor glycoprotein 130 (gp130). The structural details, as well as the exact physiological role of this interaction, remain unclear. Here, we describe the structural details of the SEA–gp130 complex by combining crosslinking mass spectrometry and computational modelling. Interestingly, SEA is not able to bind gp130-homologues from rat and mouse. Our data suggest that SEA may interact with human gp130 in a different manner than other known gp130-ligands. Moreover, the fact that SEA does not bind mouse or rat gp130 suggests that SAgs have additional mechanisms of action in humans.
30.	Diamanti, Riccardo, et al. (författare) Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase 2022 Ingår i: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 596:12, s. 1600-1610 Tidskriftsartikel (refereegranskat)abstract R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese–iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine–valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme.
31.	Encarnacao, Joao Crispim, Master, 1990-, et al. (författare) A real-time cell-binding assay reveals dynamic features of STxB-Gb3 cointernalization and STxB-mediated cargo delivery into cancer cells 2020 Ingår i: FEBS Letters. - : WILEY. - 0014-5793 .- 1873-3468. ; 594:15, s. 2406-2420 Tidskriftsartikel (refereegranskat)abstract The interaction between the Shiga toxin B-subunit (STxB) and its globotriaosylceramide receptor (Gb3) has a high potential for being exploited for targeted cancer therapy. The primary goal of this study was to evaluate the capacity of STxB to carry small molecules and proteins as cargo into cells. For this purpose, an assay was designed to provide real-time information about the StxB-Gb3 interaction as well as the dynamics and mechanism of the internalization process. The assay revealed the ability to distinguish the process of binding to the cell surface from internalization and presented the importance of receptor and STxB clustering for internalization. The overall setup demonstrated that the binding mechanism is complex, and the concept of affinity is difficult to apply. Hence, time-resolved methods, providing detailed information about the interaction of STxB with cells, are critical for the optimization of intracellular delivery.
32.	Lang, P, et al. (författare) Tartrate-resistant acid phosphatase type 5/ACP5 promotes cell cycle entry of 3T3-L1 preadipocytes by increasing IGF-1/Akt signaling 2021 Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 595:20, s. 2616-2627 Tidskriftsartikel (refereegranskat)
33.	Nicolaus, Felix, et al. (författare) Upstream charged and hydrophobic residues impact the timing of membrane insertion of transmembrane helices 2022 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 596:8, s. 1004-1012 Tidskriftsartikel (refereegranskat)abstract During SecYEG-mediated cotranslational insertion of membrane proteins, transmembrane helices (TMHs) first make contact with the membrane when their N-terminal end is ~ 45 residues away from the peptidyl transferase centre. However, we recently uncovered instances where the first contact is delayed by up to ~ 10 residues. Here, we recapitulate these effects using a model TMH fused to two short segments from the Escherichia coli inner membrane protein BtuC: a positively charged loop and a re-entrant loop. We show that the critical residues are two Arg residues in the positively charged loop and four hydrophobic residues in the re-entrant loop. Thus, both electrostatic and hydrophobic interactions involving sequence elements that are not part of a TMH can impact the way the latter behaves during membrane insertion.
34.	Raji, Olanrewaju, et al. (författare) The coordinated action of glucuronoyl esterase and α-glucuronidase promotes the disassembly of lignin–carbohydrate complexes 2021 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 595:3, s. 351-359 Tidskriftsartikel (refereegranskat)abstract Glucuronoxylans represent a significant fraction of woody biomass, and its decomposition is complicated by the presence of lignin–carbohydrate complexes (LCCs). Herein, LCCs from birchwood were used to investigate the potential coordinated action of a glucuronoyl esterase (TtCE15A) and two α-glucuronidases (SdeAgu115A and AxyAgu115A). When supplementing α-glucuronidase with equimolar quantities of TtCE15A, total MeGlcpA released after 72 h by SdeAgu115A and AxyAgu115A increased from 52% to 67%, and 61% to 95%, respectively. Based on the combined TtCE15A and AxyAgu115A activities, ~ 34% of MeGlcpA in the extracted birchwood glucuronoxylan was occupied as LCCs. Notably, insoluble LCC fractions reduced soluble α-glucuronidase concentrations by up to 70%, whereas reduction in soluble TtCE15A was less than 30%, indicating different tendencies to adsorb onto the LCC substrate.
35.	Bonne Kohler, Julie, et al. (författare) Importance of protein Ser/Thr/Tyr phosphorylation for bacterial pathogenesis 2020 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 594:15, s. 2339-2369 Forskningsöversikt (refereegranskat)abstract Protein phosphorylation regulates a large variety of biological processes in all living cells. In pathogenic bacteria, the study of serine, threonine, and tyrosine (Ser/Thr/Tyr) phosphorylation has shed light on the course of infectious diseases, from adherence to host cells to pathogen virulence, replication, and persistence. Mass spectrometry (MS)-based phosphoproteomics has provided global maps of Ser/Thr/Tyr phosphosites in bacterial pathogens. Despite recent developments, a quantitative and dynamic view of phosphorylation events that occur during bacterial pathogenesis is currently lacking. Temporal, spatial, and subpopulation resolution of phosphorylation data is required to identify key regulatory nodes underlying bacterial pathogenesis. Herein, we discuss how technological improvements in sample handling, MS instrumentation, data processing, and machine learning should improve bacterial phosphoproteomic datasets and the information extracted from them. Such information is expected to significantly extend the current knowledge of Ser/Thr/Tyr phosphorylation in pathogenic bacteria and should ultimately contribute to the design of novel strategies to combat bacterial infections.
36.	Brännström, Kristoffer, et al. (författare) The role of histidines in amyloid β fibril assembly 2017 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 591:8, s. 1167-1175 Tidskriftsartikel (refereegranskat)abstract Low pH has a strong stabilising effect on the fibrillar assembly of amyloid β, which is associated with Alzheimer's disease. The stabilising effect is already pronounced at pH 6.0, suggesting that protonation of histidines might mediate this effect. Through the systematic substitution of the three native histidines in Aβ for alanines, we have evaluated their role in fibril stability. Using surface plasmon resonance, we show that at neutral pH the fibrillar forms of all His-Ala variants are destabilised by a factor of 4-12 compared to wild-type Aβ. However, none of the His-Ala Aβ variants impair the stabilising effect of the fibril at low pH.
37.	Davies, James S, et al. (författare) Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus 2019 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:1, s. 52-66 Tidskriftsartikel (refereegranskat)abstract N‐Acetylglucosamine‐6‐phosphate deacetylase (NagA) and glucosamine‐6‐phosphate deaminase (NagB) are branch point enzymes that direct amino sugars into different pathways. For Staphylococcus aureus NagA, analytical ultracentrifugation and small‐angle X‐ray scattering data demonstrate that it is an asymmetric dimer in solution. Initial rate experiments show hysteresis, which may be related to pathway regulation, and kinetic parameters similar to other bacterial isozymes. The enzyme binds two Zn2+ ions and is not substrate inhibited, unlike the Escherichia coli isozyme. S. aureus NagB adopts a novel dimeric structure in solution and shows kinetic parameters comparable to other Gram‐positive isozymes. In summary, these functional data and solution structures are of use for understanding amino sugar metabolism in S. aureus, and will inform the design of inhibitory molecules.
38.	Farías-Rico, José Arcadio, et al. (författare) Mutational analysis of protein folding inside the ribosome exit tunnel 2017 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 591:1, s. 155-163 Tidskriftsartikel (refereegranskat)abstract Recent work has demonstrated that cotranslational folding of proteins or protein domains in, or in the immediate vicinity of, the ribosome exit tunnel generates a pulling force on the nascent polypeptide chain that can be detected using a so-called translational arrest peptide (AP) engineered into the nascent chain as a force sensor. Here, we show that AP-based force measurements combined with systematic Ala and Trp scans of a zinc-finger domain that folds in the exit tunnel can be used to identify the residues that are critical for intraribosomal folding. Our results suggest a general approach to characterize the folded state(s) that may form as a protein domain moves progressively down the ribosome exit tunnel.
39.	Ferreira, Raphael, 1990, et al. (författare) Exploiting off-targeting in guide-RNAs for CRISPR systems for simultaneous editing of multiple genes 2017 Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 591:20, s. 3288-3295 Tidskriftsartikel (refereegranskat)abstract Bioinformatics tools to design guide-RNAs (gRNAs) in Clustered Regularly Interspaced Short Palindromic Repeats systems mostly focused on minimizing off-targeting to enhance efficacy of genome editing. However, there are circumstances in which off-targeting might be desirable to target multiple genes simultaneously with a single gRNA. We termed these gRNAs as promiscuous gRNAs. Here, we present a computational workflow to identify promiscuous gRNAs that putatively bind to the region of interest for a defined list of genes in a genome. We experimentally validated two promiscuous gRNA for gene deletion, one targeting FAA1 and FAA4 and one targeting PLB1 and PLB2, thus demonstrating that multiplexed genome editing through design of promiscuous gRNA can be performed in a time and cost-effective manner.
40.	Filograna, R, et al. (författare) Mitochondrial DNA copy number in human disease: the more the better? 2021 Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 595:8, s. 976-1002 Tidskriftsartikel (refereegranskat)
41.	Garrido-Urbani, Sarah, et al. (författare) Proteomic peptide phage display uncovers novel interactions of the PDZ1-2 supramodule of syntenin 2016 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 590:1, s. 3-12 Tidskriftsartikel (refereegranskat)abstract Syntenin has crucial roles in cell adhesion, cell migration and synaptic transmission. Its closely linked postsynaptic density-95, discs large 1, zonula occludens-1 (PDZ) domains typically interact with C-terminal ligands. We profile syntenin PDZ1-2 through proteomic peptide phage display (ProP-PD) using a library that displays C-terminal regions of the human proteome. The protein recognizes a broad range of peptides, with a preference for hydrophobic motifs and has a tendency to recognize cryptic internal ligands. We validate the interaction with nectin-1 through orthogonal assays. The study demonstrates the power of ProP-PD as a complementary approach to uncover interactions of potential biological relevance.
42.	Guo, J, et al. (författare) Membrane topology and search for potential redox partners of colon cancer-specific cytochrome P450 2W1 2016 Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 590:3, s. 330-339 Tidskriftsartikel (refereegranskat)
43.	Gustafsson, Robert, et al. (författare) Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster 2017 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 591:22, s. 3781-3792 Tidskriftsartikel (refereegranskat)abstract Botulinum neurotoxins are highly toxic substances and are all encoded together with one of two alternative gene clusters, the HA or the OrfX gene cluster. Very little is known about the function and structure of the proteins encoded in the OrfX gene cluster, which in addition to the toxin contains five proteins (OrfX1, OrfX2, OrfX3, P47, and NTNH). We here present the structures of OrfX2 and P47, solved to 2.1 and 1.8 Å, respectively. We show that they belong to the TULIP protein superfamily, which are often involved in lipid binding. OrfX1 and OrfX2 were both found to bind phosphatidylinositol lipids.
44.	Kahle, Maximilian, et al. (författare) Insights into the mechanism of nitric oxide reductase from a Fe-B-depleted variant 2019 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 593:12, s. 1351-1359 Tidskriftsartikel (refereegranskat)abstract A key step of denitrification, the reduction of toxic nitric oxide to nitrous oxide, is catalysed by cytochrome c-dependent NO reductase (cNOR). cNOR contains four redox-active cofactors: three hemes and a nonheme iron (Fe-B). Heme b(3) and Fe-B constitute the active site, but the specific mechanism of NO-binding events and reduction is under debate. Here, we used a recently constructed, fully folded and hemylated cNOR variant that lacks Fe-B to investigate the role of Fe-B during catalysis. We show that in the Fe-B-less cNOR, binding of both NO and O-2 to heme b(3) still occurs but further reduction is impaired, although to a lesser degree for O-2 than for NO. Implications for the catalytic mechanisms of cNOR are discussed.
45.	Lee, Seoeun, et al. (författare) The Mgr2 subunit of the TIM23 complex regulates membrane insertion of marginal stop-transfer signals in the mitochondrial inner membrane 2020 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 594:6, s. 1081-1087 Tidskriftsartikel (refereegranskat)abstract The TIM23 complex mediates membrane insertion of presequence-containing mitochondrial proteins via a stop-transfer mechanism. Stop-transfer signals consist of hydrophobic transmembrane segments and flanking charges. Mgr2 functions as a lateral gatekeeper of the TIM23 complex. However, it remains elusive which features of stop-transfer signals are discriminated by Mgr2. To determine the effects of Mgr2 on the TIM23-mediated stop-transfer pathway, we measured membrane insertion of model transmembrane segments of varied hydrophobicity and flanking charges in Mgr2-deletion or -overexpression yeast strains. We found that upon deletion of Mgr2, the threshold hydrophobicity for membrane insertion, as well as the requirement for matrix-facing positive charges, is reduced. These results imply that the Mgr2-mediated gatekeeper function is important for controlling membrane sorting of marginal stop-transfer signals.
46.	Liu, Jingyi, et al. (författare) Giardia intestinalis cystatin is a potent inhibitor of papain, parasite cysteine proteases and, to a lesser extent, human cathepsin B 2019 Ingår i: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 593:12, s. 1313-1325 Tidskriftsartikel (refereegranskat)abstract Cystatins are important regulators of papain-like cysteine proteases. In the protozoan parasite Giardia intestinalis, papain-like cysteine proteases play an essential role in the parasite's biology and pathogenicity. Here, we characterized a cysteine protease inhibitor of G. intestinalis that belongs to type-I-cystatins. The parasite cystatin is shown to be a strong inhibitor of papain (K-i approximate to 0.3 nm) and three parasite cysteine proteases (CP14019, CP16160 and CP16779, K-i approximate to 0.9-5.8 nm), but a weaker inhibitor of human cathepsin B (K-i approximate to 79.9 nm). The protein localizes mainly in the cytoplasm. Together, these data suggest that cystatin of G. intestinalis plays a role in the regulation of cysteine protease activities in the parasite and, possibly, in the interaction with the host.
47.	Lundin, Camilla Rydström, et al. (författare) Modulation of O-2 reduction in Saccharomyces cerevisiae mitochondria 2017 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 591:24, s. 4049-4055 Tidskriftsartikel (refereegranskat)abstract Respiratory supercomplex factor (Rcf) 1 is a membrane-bound protein that modulates the activity of cytochrome c oxidase (CytcO) in Saccharomycescerevisiae mitochondria. To investigate this regulatory mechanism, we studied the interactions of CytcO with potassium cyanide (KCN) upon removal of Rcf Delta. While the addition of KCN to the wild-type mitochondria results in a full reduction of heme a, with the rcf Delta mitochondria, a significant fraction remains oxidized. Upon addition of ascorbate in the presence of O-2 and KCN, the reduction level of hemes a and b was a factor of similar to 2 larger with the wild-type than with the rcf Delta mitochondria. These data indicate that turnover of CytcO was less blocked in rcf Delta than in the wild-type mitochondria, suggesting that Rcf Delta modulates the structure of the catalytic site.
48.	Marino, Jacopo, et al. (författare) Small protein domains fold inside the ribosome exit tunnel 2016 Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 590:5, s. 655-660 Tidskriftsartikel (refereegranskat)abstract Cotranslational folding of small protein domains within the ribosome exit tunnel may be an important cellular strategy to avoid protein misfolding. However, the pathway of cotranslational folding has so far been described only for a few proteins, and therefore, it is unclear whether folding in the ribosome exit tunnel is a common feature for small protein domains. Here, we have analyzed nine small protein domains and determined at which point during translation their folding generates sufficient force on the nascent chain to release translational arrest by the SecM arrest peptide, both in vitro and in live E. coli cells. We find that all nine protein domains initiate folding while still located well within the ribosome exit tunnel.
49.	Martinez Molledo, M, et al. (författare) Tripeptide binding in a proton-dependent oligopeptide transporter 2018 Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 592:19, s. 3239-3247 Tidskriftsartikel (refereegranskat)
50.	Mutz, CN, et al. (författare) EWS-FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway 2016 Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 590:14, s. 2063-2075 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)

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