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1.	Abdrakhmanov, A, et al. (författare) Involvement of mitophagy in cisplatin-induced cell death regulation 2019 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1437-4315 .- 1431-6730. ; 400:2, s. 161-170 Tidskriftsartikel (refereegranskat)abstract Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. The removal of malfunctioning or damaged mitochondria is essential for normal cellular physiology and tissue development. Stimulation of mitochondrial permeabilization and release of proapoptotic factors from the intermembrane space is an essential step in triggering the mitochondrial pathway of cell death. In this study, we analyzed the extent to which mitophagy interferes with cell death, attenuating the efficiency of cancer therapy. We show that stimulation of mitophagy suppressed cisplatin-induced apoptosis, while mitophagy inhibition stimulates apoptosis and autophagy. Suppression of mitophagy involved production of reactive oxygen species, and the fate of cell was dependent on the interplay between endoplasmic reticulum stress and autophagy.
2.	Appelros, Stefan, et al. (författare) Studies on the turnover of procarboxypeptidase B, its active enzyme and the activation peptide in the pig 1998 Ingår i: Biological Chemistry. - : Walter de Gruyter GmbH. - 1437-4315. ; 379:7, s. 893-898 Tidskriftsartikel (refereegranskat)abstract Recent developments in the treatment of acute pancreatitis have focused on the importance of early determination of the severity of an attack. Measuring levels of activation peptides from pancreatic proenzymes seems to be one way to predict severity. Levels of the activation peptide from procarboxypeptidase B, in both serum and urine on admission, have been shown to correlate to the outcome. To be able to interpret levels of this peptide in serum and urine under normal and in various acute abdominal conditions, we need knowledge about its turnover in the circulation. Procarboxypeptidase B, active carboxypeptidase and the activation peptide were therefore purified from porcine pancreatic juice. These proteins were labelled with 125I or 131I and their turnovers were studied in vivo in the pig. The proenzyme and the activation peptide were eliminated without interaction with any substance in the circulation. The active enzyme was to some degree bound to a substance with a molecular mass of 10-20 kDa. Active CPB was eliminated more slowly than proCPB and the activation peptide. Five percent of the activation peptide was detected nondegraded in the urine. After intraduodenal administration of the activation peptide there was no sign of the peptide in the urine.
3.	Arampatzidou, Maria, et al. (författare) Effects of cathepsin K deficiency on intercellular junction proteins, luminal mucus layers, and extracellular matrix constituents in the mouse colon. 2012 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1437-4315. ; 393:12, s. 1391-403 Tidskriftsartikel (refereegranskat)abstract Cathepsin K has been shown to exhibit antimicrobial and anti-inflammatory activities in the mouse colon. To further elucidate its role, we used Ctsk-/- mice and demonstrated that the absence of cathepsin K was accompanied by elevated protein levels of related cysteine cathepsins (cathepsins B, L, and X) in the colon. In principle, such changes could result in altered subcellular localization; however, the trafficking of cysteine cathepsins was not affected in the colon of Ctsk-/- mice. However, cathepsin K deficiency affected the extracellular matrix constituents, as higher amounts of collagen IV and laminin were observed. Moreover, the localization pattern of the intercellular junction proteins E-cadherin and occludin was altered in the colon of Ctsk-/- mice, suggesting potential impairment of the barrier function. Thus, we used an ex vivo method for assessing the mucus layers and showed that the absence of cathepsin K had no influence on mucus organization and growth. The data of this study support the notion that cathepsin K contributes to intestinal homeostasis and tissue architecture, but the lack of cathepsin K activity is not expected to affect the mucus-depending barrier functions of the mouse colon. These results are important with regard to oral administration of cathepsin K inhibitors that are currently under investigation in clinical trials.
4.	Aspenstrom, P (författare) Atypical Rho GTPases RhoD and Rif integrate cytoskeletal dynamics and membrane trafficking 2014 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1437-4315 .- 1431-6730. ; 395:5, s. 477-484 Tidskriftsartikel (refereegranskat)abstract The Rho GTPases are essential regulators of basic cellular processes, including cell migration, cell contraction and cell division. Most studies still involve just the three canonical members, RhoA, Rac1 and Cdc42, although the Rho GTPases comprise at least 20 members. The aim of this review is to highlight some of the recent advances in our knowledge regarding the less-studied Rho members, with the focus on RhoD and Rif. The phenotypic alterations to cell behaviour that are triggered by RhoD and Rif suggest that they have unique impacts on cytoskeletal dynamics that distinguish them from the well-studied members of the Rho GTPases. In addition, RhoD has a role in the regulation of intracellular transport of vesicles. Taken together, the available data indicate that RhoD and Rif have functions as master regulators in the integration of cytoskeletal reorganisation and membrane trafficking.
5.	Barlow, T, et al. (författare) RNase E, the major player in mRNA degradation, is down-regulated in Escherichia coli during a transient growth retardation (diauxic lag) 1998 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 379:1, s. 33-38 Tidskriftsartikel (refereegranskat)
6.	Bjorkqvist, J, et al. (författare) Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents 2013 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1437-4315. ; 394:9, s. 1195-1204 Tidskriftsartikel (refereegranskat)abstract Contact to polyanions induces autoactivation of the serine protease factor XII that triggers the kallikrei-kinin system. Recent studies indicate that polysaccharide-induced autoactivation of factor XII has a role in allergy-related vascular leakage, and angioedema. Here, we characterize in vivo effects of the synthetic polysaccharide dextran sulfate in human plasma and in rodent models. Minute amounts of high-molecular-weight dextran sulfate-initiated factor XII-autoactivation and triggered formation of the inflammatory mediator bradykinin via plasma kallikrein-mediated cleavage of high-molecular-weight kininogen. High-molecular-weight kininogen fragments, containing the HKH20 sequence in domain D5H, blocked dextran sulfate-initiated bradykinin-generation by depleting plasma Zn2+ ions. Topical application of high molecular weight dextran sulfate increased leakage in murine skin microvessels, in a bradykinin-dependent manner. Intravital laser scanning microscopy showed a greater than two-fold elevated and accelerated fluid extravasation in C1 esterase inhibitor deficient mice that lack the major inhibitor of factor XII, compared to wild-type controls. Intra-arterial infusion of dextran sulfate induced a rapid transient drop in arterial blood pressure in rats and preinjection of kinin B2 receptor antagonists or HKH20 peptide blunted dextran sulfate-triggered hypotensive reactions. The data characterize dextran sulfate as a potent in vivo activator of factor XII with implications for bradykinin-mediated vascular permeability and blood pressure control.
7.	Brännström, Kristoffer, et al. (författare) Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis 2012 Ingår i: Biological chemistry (Print). - : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 393:5, s. 369-377 Tidskriftsartikel (refereegranskat)abstract SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH.
8.	de Veer, Simon J., et al. (författare) Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors 2016 Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 397:12, s. 1237-1249 Tidskriftsartikel (refereegranskat)abstract Kallikrein-related peptidase 5 (KLK5) is a promising therapeutic target in several skin diseases, including Netherton syndrome, and is emerging as a potential target in various cancers. In this study, we used a sparse matrix library of 125 individually synthesized peptide substrates to characterize the binding specificity of KLK5. The sequences most favored by KLK5 were GRSR, YRSR and GRNR, and we identified sequence-specific interactions involving the peptide N-terminus by analyzing kinetic constants (k(cat) and K-M) and performing molecular dynamics simulations. KLK5 inhibitors were subsequently engineered by substituting substrate sequences into the binding loop (P1, P2 and P4 residues) of sunflower trypsin inhibitor-1 (SFTI-1). These inhibitors were effective against KLK5 but showed limited selectivity, and performing a further substitution at P2' led to the design of a new variant that displayed improved activity against KLK5 (K-i = 4.2 +/- 0.2 nm), weak activity against KLK7 and 12-fold selectivity over KLK14. Collectively, these findings provide new insight into the design of highly favored binding sequences for KLK5 and reveal several opportunities for modulating inhibitor selectivity over closely related proteases that will be useful for future studies aiming to develop therapeutic molecules targeting KLK5.
9.	Ellencrona, Karin, et al. (författare) Flavivirus NS5 associates with host-cell proteins zonula occludens-1 (ZO-1) and regulating synaptic membrane exocytosis-2 (RIMS2) via an internal PDZ binding mechanism 2009 Ingår i: Biological chemistry (Print). - Berlin : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 390:4, s. 319-323 Tidskriftsartikel (refereegranskat)abstract Dengue virus (DENV) and tick-borne encephalitis virus (TBEV) are flaviviruses, which can cause lethal hemorrhagic fever and encephalitis, respectively. Here, we demonstrate that the TBEV-NS5 and DENV-NS5 proteins use an internal binding mechanism to target human PDZ proteins. TBEV-NS5 has high affinity to regulating synaptic membrane exocytosis-2 (RIMS2) and Scribble, whereas DENV-NS5 binds primarily to the tight junction protein zonula occludens-1 (ZO-1). Targeting of TBEV-NS5 to the plasma membrane is stabilised by ZO-1; however, DENV-NS5 co-localises with ZO-1 in the nucleus. These interactions have potential important roles in the ability of flaviviruses to manipulate cell proliferation, junction permeability and the interferon pathways.
10.	Faroldi, Gianni, et al. (författare) ADAMTS: Novel proteases expressed by activated mast cells 2013 Ingår i: Biological Chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 394, s. 291-305 Tidskriftsartikel (refereegranskat)abstract Here we show that mast cells (MCs) express the metalloproteases of the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, and that ADAMTS expression is influenced by MC activation. Co-culture of MCs with live Gram-positive bacteria caused a profound induction of ADAMTS-9 and -6, as well as down-regulated expression of ADAMTS-5. Similar patterns were also seen after MC activation with calcium ionophore and by immunoglobulin E receptor crosslinking. Moreover, ADAMTS-5, -6 and -9 were all induced by activation of terminally differentiated murine peritoneal MCs and in a human MC line. ADAMTS-9 up-regulation in response to immunoglobulin E receptor crosslinking was strongly dependent on Go6976-sensitive protein kinase C and partly dependent on nuclear factor of activated T cells and nuclear factor kappa-light-chain-enhancer of activated B cells, respectively. The expression of ADAMTS-5, -6 and -9 was closely linked to MC maturation, as shown by their strong induction during the differentiation of bone marrow precursor cells into mature MCs. ADAMTS family members have been shown to possess aggrecanase activity. Accordingly, MCs were shown to express aggrecanase activity. Finally, ADAMTS-5 protein was detected in MCs by immunocytochemistry. Taken together, the present study reveals ADAMTS expression by MCs and that MC activation regulates the expression of these proteases, thus implicating the ADAMTS family of proteases in MC function.
11.	Fu, Zhirong, et al. (författare) Marked difference in efficiency of the digestive enzymes pepsin, trypsin, chymotrypsin, and pancreatic elastase to cleave tightly folded proteins 2021 Ingår i: Biological chemistry (Print). - : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 402:7, s. 861-867 Tidskriftsartikel (refereegranskat)abstract In order for the intestinal mucosa to absorb dietary proteins they have to be digested into single amino acids or very short peptides of a length of not more than four amino acids. In order to study the efficiency of the digestive endopeptidases to digest folded proteins we have analyzed several target proteins under different conditions, native proteins, heat denatured and acid treated. The three pancreatic serine proteases, trypsin, chymotrypsin, and pancreatic elastase, were found to be remarkable inefficient in cleaving native folded proteins whereas pepsin, which acts at a very low pH (pH 1.2) was much more efficient, possibly due to the denaturing conditions and thereby better accessibility to internal cleavage sites at the low pH. Heat treatment improved the cleavage considerably by all three pancreatic enzymes, but acid treatment followed by return to neutral pH did not have any major effect. Cleavage at the low pH when the protein is in a denatured state, is apparently very efficient. This indicates that pepsin is the prime enzyme cleaving the properly folded native proteins and that the pancreatic enzymes primarily are involved in generating single amino acids or very short peptides for efficient uptake by the intestinal mucosa.
12.	Haddada, Meriem, et al. (författare) Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype 2018 Ingår i: Biological chemistry (Print). - : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 399:9, s. 1099-1105 Tidskriftsartikel (refereegranskat)abstract We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of alpha 5/beta 1/alpha v/beta 3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.
13.	Hellman, Lars, et al. (författare) Granule proteases of hematopoietic cells, a family of versatile inflammatory mediators - an update on their cleavage specificity, in vivo substrates, and evolution 2014 Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 395:1, s. 15-49 Forskningsöversikt (refereegranskat)abstract Cells from several of the hematopoietic cell lineages including mast cells, basophils, neutrophils, cytotoxic T cells, and natural killer (NK) cells store proteases at very high levels within their cytoplasmic granules. In mast cells, these proteases can account for up to 35% of the total cellular protein, and the absolute majority of these belong to the chymotrypsin-related serine protease family. A number of very diverse functions have been identified for these proteases, including apoptosis induction, blood pressure regulation, inactivation of insect and snake toxins, intestinal parasite expulsion, killing of bacteria and fungi, induction, mobilization, or degradation of cytokines, and the degradation of connective tissue components. A very broad spectrum of primary cleavage specificities has also been observed, including chymase, tryptase, asp-ase, elastase, and met-ase specificities, which highlights the large flexibility in the active site of these proteases. Mast cells primarily express chymases and tryptases with chymotryptic or tryptic primary cleavage specificities, respectively. Neutrophils have several enzymes with chymase, elastase, and tryptase specificities. T cells and NK cells express between 5 and 14 different granzymes, depending on the species, and these enzymes have tryptase, asp-ase, chymase, and met-ase specificities. This review focuses on the appearance of these proteases during vertebrate evolution, their primary and extended cleavage specificities, and their potential in vivo substrates. The in vivo substrates and functions are a particular challenging issue because several of these enzymes have a relatively broad specificity and may therefore cleave a wide range of different substrates.
14.	Hernandez-Cortes, Patricia, et al. (författare) Trypsin from Pacifastacus leniusculus hepatopancreas: Purification and cDNA cloning of the synthesized zymogen 1999 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 380:4, s. 499-501 Tidskriftsartikel (refereegranskat)abstract Trypsin was purified from crayfish, Pacifastacus leniusculus, hepatopancreas, and the gene that encoded this enzyme was cloned from a hepatopancreas cDNA library. Crayfish trypsin is synthesized as a zymogen according to the sequence of the putative precu
15.	Hofer, T, et al. (författare) Hydrogen peroxide causes greater oxidation in cellular RNA than in DNA 2005 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 386:4, s. 333-337 Tidskriftsartikel (refereegranskat)
16.	Holmberg, Lovisa, et al. (författare) Release of ribosome-bound 5S rRNA upon cleavage of the phosphodiester bond between nucleotides A54 and A55 in 5S rRNA 2000 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 381:11, s. 1041-1046 Tidskriftsartikel (refereegranskat)abstract Reticulocyte lysates contain ribosome-bound and free populations of 5S RNA. The free population is sensitive to nuclease cleavage in the internal loop B, at the phosphodiester bond connecting nucleotides A54 and A55. Similar cleavage sites were detected in 5S rRNA in 60S subunits and 80S ribosomes. However, 5S rRNA in reticulocyte polysomes is insensitive to cleavage unless ribosomes are salt-washed. This suggests that a translational factor protects the backbone surrounding A54 from cleavage in polysomes. Upon nuclease treatment of mouse 60S subunits or reticulocyte lysates a small population of ribosomes released its 5S rRNA together with ribosomal protein L5. Furthermore, rRNA sequences from 5.8S, 28S and 18S rRNA were released. In 18S rRNA the sequences mainly originate from the 630 loop and stem (helix 18) in the 5' domain, whereas in 28S rRNA a majority of fragments is derived from helices 47 and 81 in domains III and V, respectively. We speculate that this type of rRNA-fragmentation may mimic a ribosome degradation pathway.
17.	Hu, Jiaxin, et al. (författare) Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs 2011 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 392:4, s. 315-325 Tidskriftsartikel (refereegranskat)abstract Spinocerebellar ataxia-3 (also known as Machado-Joseph disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 (ATX3) protein. Inhibiting expression of ATX3 would provide a therapeutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We have now identified additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the conjugated cation chain. We can also achieve potent and selective inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation.
18.	Jacobsen, Marc, et al. (författare) Novel strategies to identify biomarkers in tuberculosis 2008 Ingår i: Biological chemistry (Print). - Berlin, Germany : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 389:5, s. 487-95 Tidskriftsartikel (refereegranskat)abstract The more we learn about the immune response against tuberculosis (TB) and particularly about the features which distinguish protective immunity, disease susceptibility and pathology, the better we can define biomarkers which correlate with these different stages of infection. The most widely used biomarker in TB, which without a doubt is an important component of protective immunity, is IFNgamma secreted by antigen-specific CD4 T-cells. However, the complexity of the immune response against TB makes it more than likely that additional biomarkers are required for a reliable correlate of protection. As a corollary, we assume that a set of biomarkers will be required, termed a biosignature.
19.	Kemp, Grant, et al. (författare) Small membrane proteins - elucidating the function of the needle in the haystack 2014 Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 395:12, s. 1365-1377 Forskningsöversikt (refereegranskat)abstract Membrane proteins are important mediators between the cell and its environment or between different compartments within a cell. However, much less is known about the structure and function of membrane proteins compared to water-soluble proteins. Moreover, until recently a subset of membrane proteins, those shorter than 100 amino acids, have almost completely evaded detection as a result of technical difficulties. These small membrane proteins (SMPs) have been underrepresented in most genomic and proteomic screens of both pro-and eukaryotic cells and, hence, we know much less about their functions in both. Currently, through a combination of bioinformatics, ribosome profiling, and more sensitive proteomics, large numbers of SMPs are being identified and characterized. Herein we describe recent advances in identifying SMPs from genomic and proteomic datasets and describe examples where SMPs have been successfully characterized biochemically. Finally we give an overview of identified functions of SMPs and speculate on the possible roles SMPs play in the cell.
20.	Kohler, Verena, et al. (författare) Hsp70-mediated quality control : should I stay or should I go? 2020 Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 401:11, s. 1233-1248 Forskningsöversikt (refereegranskat)abstract Chaperones of the 70 kDa heat shock protein (Hsp70) superfamily are key components of the cellular proteostasis system. Together with its co-chaperones, Hsp70 forms proteostasis subsystems that antagonize protein damage during physiological and stress conditions. This function stems from highly regulated binding and release cycles of protein substrates, which results in a flow of unfolded, partially folded and misfolded species through the Hsp70 subsystem. Specific factors control how Hsp70 makes decisions regarding folding and degradation fates of the substrate proteins. In this review, we summarize how the flow of Hsp70 substrates is controlled in the cell with special emphasis on recent advances regarding substrate release mechanisms.
21.	Kulikov, AV, et al. (författare) Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death 2016 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1437-4315 .- 1431-6730. ; 397:7, s. 661-670 Tidskriftsartikel (refereegranskat)abstract Cardiac glycosides (CGs) or cardiotonic steroids, which constitute a group of naturally occurring compounds with a steroid-like structure, can act on Na+/K+-ATPase as a receptor and activate intracellular signaling messengers leading to a variety of cellular responses. Epidemiological studies have revealed that CGs, used for the treatment of cardiac disorders, may also be beneficial as anti-cancer agents. CGs, acting in combination with other chemotherapeutic agents, may significantly alter their efficiency in relation to cancer cell elimination, causing both sensitization and an increase in cancer cell death, and in some cases resistance to chemotherapy. Here we show the ability of CGs to modulate apoptotic response to conventionally used anti-cancer drugs. In combination with etoposide, CGs digoxin may enhance cytotoxic potential, thereby allowing the chemotherapeutic dose to be decreased and minimizing toxicity and adverse reactions. Mechanisms behind this event are discussed.
22.	Lilie, Hauke, et al. (författare) Polyionic and cysteine-containing fusion peptides as versatile protein tags 2013 Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 394:8, s. 995-1004 Forskningsöversikt (refereegranskat)abstract In response to advances in proteomics research and the use of proteins in medical and biotechnological applications, recombinant protein production and the design of specific protein characteristics and functions has become a widely used technology. In this context, protein fusion tags have been developed as indispensable tools for protein expression, purification, and the design of functionalized surfaces or artificially bifunctional proteins. Here we summarize how positively or negatively charged polyionic fusion peptides with or without an additional cysteine can be used as protein tags for protein expression and purification, for matrix-assisted refolding of aggregated protein, and for coupling of proteins either to technologically relevant matrices or to other proteins. In this context we used cysteine-containing polyionic fusion peptides for the design of immunotoxins. In general, polyionic fusion tags can be considered as a multifunctional module in protein technology.
23.	Löw, Christian, et al. (författare) Structural basis for PTPA interaction with the invariant C-terminal tail of PP2A 2014 Ingår i: Biological chemistry (Print). - : Walter de Gruyter. - 1431-6730 .- 1437-4315. ; 395:7-8, s. 881-889 Tidskriftsartikel (refereegranskat)abstract Protein phosphatase 2A (PP2A) is a highly abundant heterotrimeric Ser/Thr phosphatase involved in the regulation of a variety of signaling pathways. The PP2A phosphatase activator (PTPA) is an ATP-dependent activation chaperone, which plays a key role in the biogenesis of active PP2A. The C-terminal tail of the catalytic subunit of PP2A is highly conserved and can undergo a number of posttranslational modifications that serve to regulate the function of PP2A. Here we have studied structurally the interaction of PTPA with the conserved C-terminal tail of the catalytic subunit carrying different posttranslational modifications. We have identified an additional interaction site for the invariant C-terminal tail of the catalytic subunit on PTPA, which can be modulated via posttranslational modifications. We show that phosphorylation of Tyr307(PP2A-C) or carboxymethylation of Leu309(PP2A-C) abrogates or diminishes binding of the C-terminal tail, whereas phosphorylation of Thr304(PP2A-C) is of no consequence. We suggest that the invariant C-terminal residues of the catalytic subunit can act as affinity enhancer for different PP2A interaction partners, including PTPA, and a different code of posttranslational modifications can favour interactions to one subunit over others.
24.	Meister, Sebastian, et al. (författare) Directed evolution of the 3C protease from coxsackievirus using a novel fluorescence-assisted intracellular method 2019 Ingår i: Biological chemistry (Print). - : WALTER DE GRUYTER GMBH. - 1431-6730 .- 1437-4315. ; 400:3, s. 405-415 Tidskriftsartikel (refereegranskat)abstract Proteases are crucial for regulating biological processes in organisms through hydrolysis of peptide bonds. Recombinant proteases have moreover become important tools in biotechnological, and biomedical research and as therapeutics. We have developed a label-free high-throughput method for quantitative assessment of proteolytic activity in Escherichia coli. The screening method is based on co-expression of a protease of interest and a reporter complex. This reporter consists of an aggregation-prone peptide fused to a fluorescent protein via a linker that contains the corresponding substrate sequence. Cleavage of the substrate rescues the fluorescent protein from aggregation, resulting in increased fluorescence that correlates to proteolytic activity, which can be monitored using flow cytometry. In one round of flow-cytometric cell sorting, we isolated an efficiently cleaved tobacco etch virus (TEV) substrate from a 1:100 000 background of non-cleavable sequences, with around 6000-fold enrichment. We then engineered the 3C protease from coxsackievirus B3 (CVB3 3C(pro)) towards improved proteolytic activity on the substrate LEVLFQ down arrow GP. We isolated highly proteolytic active variants from a randomly mutated CVB3 3C(pro) library with up to 4-fold increase in activity. The method enables simultaneous measurement of proteolytic activity and protease expression levels and can therefore be applied for protease substrate profiling, as well as directed evolution of proteases.
25.	Pejler, Gunnar, et al. (författare) Mast cells express tyrosine hydroxylase and store dopamine in a serglycin-dependent manner 2012 Ingår i: Biological Chemistry. - 1431-6730 .- 1437-4315. ; 393, s. 107-112 Tidskriftsartikel (refereegranskat)abstract Here we show that mast cells contain dopamine and that mast cell activation causes dopamine depletion, indicating its presence within secretory granules. Dopamine storage increased during mast cell maturation from bone marrow precursors, and was dependent on the presence of serglycin. Moreover, the expression of tyrosine hydroxylase, the key enzyme in dopamine biosynthesis, was induced during mast cell maturation; histidine decarboxylase and tryptophan hydroxylase 1 were also induced. Mast cell activation caused a robust induction of histidine decarboxylase, but no stimulation of tyrosine hydroxylase or tryptophan hydroxylase 1 expression. The present study points toward a possible role of dopamine in mast cell function.
26.	Qadri, Fatimunnisa, et al. (författare) Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors 2016 Ingår i: Biological Chemistry. - : Walter de Gruyter GmbH. - 1437-4315 .- 1431-6730. ; 397:2, s. 97-109 Tidskriftsartikel (refereegranskat)abstract Bradykinin (BK) and des-Arg(9)-BK are pro-inflammatory mediators acting via B2 (B2R) and B1 (B1R) receptors, respectively. We investigated the role of B2R and B1R in lipopolysaccharide (LPS)-induced hypothalamopituitary-adrenal (HPA) axis activation in SD rats. LPS given intraperitoneally (ip) up-regulated B1R mRNA in the hypothalamus, both B1R and B2R were up-regulated in pituitary and adrenal glands. Receptor localization was performed using immunofluorescence staining. B1R was localized in the endothelial cells, nucleus supraopticus (SON), adenohypophysis and adrenal cortex. B2R was localized nucleus paraventricularis (PVN) and SON, pituitary and adrenal medulla. Blockade of B1R prior to LPS further increased ACTH release and blockade of B1R 1 h after LPS decreased its release. In addition, we evaluated if blockade of central kinin receptors influence the LPS-induced stimulation of hypothalamic neurons. Blockade of both B1R and B2R reduced the LPS-induced c-Fos immunoreactivity in the hypothalamus. Our data demonstrate that a single injection of LPS induced a differential expression pattern of kinin B1R and B2R in the HPA axis. The tissue specific cellular localization of these receptors indicates that they may play a crucial role in the maintenance of body homeostasis during endotoxemia.
27.	Risse, SL, et al. (författare) SH3-mediated targeting of Wrch1/RhoU by multiple adaptor proteins 2013 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1437-4315. ; 394:3, s. 421-432 Tidskriftsartikel (refereegranskat)abstract Wrch1/RhoU is an atypical member of the Rho family. A major structural difference is the extended N-terminus of Wrch1 (nWrch1) containing three putative SH3 domain-binding motifs whose specificities are unknown. To define the impact of this extended region on coupling Wrch1 to cellular signaling, we analyzed in this study nWrch1 interaction with Src homology 3 (SH3) domains of different adaptor proteins. Using sedimentation and isothermal titration calorimetric (ITC) measurements, we identified isolated SH3 domains of growth factor receptor-bound protein 2 (Grb2), noncatalytic region of tyrosine kinase adaptor protein 1 (Nck1), c-Src, chicken tumor virus no. 10 (CT 10) regulator kinase 1 (Crk1), and p120 as low-affinity Wrch1-binding partners. Interestingly, under cell-based conditions, nWrch1 bound tightly to endogenous Grb2 and Nck, but not to Crk, c-Src, or p120. Consistent with this, a very tight nWrch1 interaction with full-length Grb2 and Nck1 was confirmed in vitro by ITC measurements indicating that high avidity of the adaptor proteins can compensate for the low affinity of their SH3 domains. Peptide analysis revealed that the central PxxP motif of nWrch1, which employs a minimal consensus sequence of eight amino acids with an essential arginine next to the PxxP motif, is responsible for these interactions. Thus, novel functional insights from this study suggest that multiple upstream signals may converge on Wrch1 directly through its SH3 domain-binding properties.
28.	Sloma, Marika Salonen, et al. (författare) Chemical accessibility of 18S rRNA in native ribosomal complexes : Interaction sites of mRNA, tRNA and translation factors 2001 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 382:4, s. 661-668 Tidskriftsartikel (refereegranskat)abstract During protein synthesis the ribosome interacts with ligands such as mRNA, tRNA and translation factors. We have studied the effect of ribosome-ligand interaction on the accessibility of 18S rRNA for single strand-specific modification in ribosomal complexes that have been assembled in vivo, i. e. native polysomes. A comparison of the modification patterns derived from programmed and non-programmed ribosomes showed that bases in the 630- and 1060-loops (530- and 790-loops in E. coli) together with two nucleotides in helices 33 and 34 were protected from chemical modification. The majority of the protected sites were homologous to sites previously suggested to be involved in mRNA and/or tRNA binding in prokaryotes and eukaryotes, implying that the interaction sites for these ligands are similar, if not identical, in naturally occurring programmed ribosomes and in in vitro assembled ribosomal complexes. Additional differences between programmed and non-programmed ribosomes were found in hairpin 8. The bases in helix 8 showed increased exposure to chemical modification in the programmed ribosomes. In addition, structural differences in helices 36 and 37 were observed between native 80S run-off ribosomes and 80S ribosomes assembled from isolated 40S and 60S subunits.
29.	Stefansson, Kristina, et al. (författare) Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum. 2006 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 387:6, s. 761-768 Tidskriftsartikel (refereegranskat)
30.	Steinbacher, S, et al. (författare) Interaction of Salmonella phage P22 with its O-antigen receptor studied by X-ray crystallography 1997 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 378:3-4, s. 337-343 Tidskriftsartikel (refereegranskat)
31.	Tedelind, Sofia, et al. (författare) Nuclear cysteine cathepsin variants in thyroid carcinoma cells 2010 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 391:8, s. 923-935 Tidskriftsartikel (refereegranskat)abstract The cysteine peptidase cathepsin B is important in thyroid physiology by being involved in thyroid prohormone processing initiated in the follicular lumen and completed in endo-lysosomal compartments. However, cathepsin B has also been localized to the extrafollicular space and is therefore suggested to promote invasiveness and metastasis in thyroid carcinomas through, e. g., ECM degradation. In this study, immunofluorescence and biochemical data from subcellular fractionation revealed that cathepsin B, in its single- and two-chain forms, is localized to endo-lysosomes in the papillary thyroid carcinoma cell line KTC-1 and in the anaplastic thyroid carcinoma cell lines HTh7 and HTh74. This distribution is not affected by thyroid stimulating hormone (TSH) incubation of HTh74, the only cell line that expresses a functional TSH-receptor. Immunofluorescence data disclosed an additional nuclear localization of cathepsin B immunoreactivity. This was supported by biochemical data showing a proteolytically active variant slightly smaller than the cathepsin B proform in nuclear fractions. We also demonstrate that immunoreactions specific for cathepsin V, but not cathepsin L, are localized to the nucleus in HTh74 in peri-nucleolar patterns. As deduced from co-localization studies and in vitro degradation assays, we suggest that nuclear variants of cathepsins are involved in the development of thyroid malignancies through modification of DNA-associated proteins.
32.	Torrents, Eduard, et al. (författare) Antibacterial activity of radical scavengers against reductase from Bacillus anthracis 2010 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 391:2/3, s. 229-234 Tidskriftsartikel (refereegranskat)abstract Bacillus anthracis is a severe mammalian pathogen. The deoxyribonucleotides necessary for DNA replication and repair are provided via the ribonucleotide reductase (RNR) enzyme. RNR is also important for spore germination and cell proliferation upon infection. We show that the expression of B. anthracis class Ib RNR responds to the environment that the pathogen encounters upon infection. We also show that several anti-proliferative agents (radical scavengers) specifically inhibit the B. anthracis RNR. Owing to the importance of RNR in the pathogenic infection process, our results highlight a promising potential to inhibit the growth of B. anthracis early during infection.
33.	Trouillon, Raphaël, 1982 (författare) Biological applications of the electrochemical sensing of nitric oxide: fundamentals and recent developments 2013 Ingår i: Biological chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 394:1, s. 17-33 Tidskriftsartikel (refereegranskat)abstract Nitric oxide (NO) is a unique cellular messenger linked to a number of important biological processes. Its free radical nature, small size and fast diffusivity make it highly reactive and membrane permeable. Unfortunately, its reactivity, coupled with the inherent complexity of in situ biological measurements, makes it a challenge to detect. For the past 20 years, electrochemical methods have been used to investigate the role of NO in a number of biological processes, including vascular physiology, immune response, neuronal mediation, tissue growth and oxidative stress. This review examines the biological applications of electrochemical NO sensors and the technologies used to elucidate different physiological phenomena associated with this unique biomolecule with a specific focus on the developments and innovations reported in the last 3 years.
34.	Van Kuilenburg, André B P, et al. (författare) Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function 2005 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 386:4, s. 319-324 Tidskriftsartikel (refereegranskat)abstract Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene ( DPYD ) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11 + 1G-->T and the missense mutations 731A-->C (E244V) and 1651G-->A (A551T). The G-->T mutation in the invariant GT splice donor site flanking exon 11 (IVS11 + 1G-->T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400-446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.
35.	Waern, Ida, et al. (författare) Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan-serine protease axis 2012 Ingår i: Biological chemistry (Print). - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 393:12, s. 1555-1567 Tidskriftsartikel (refereegranskat)abstract Mast cell (MC) granules contain large amounts of proteases of the chymase, tryptase and carboxypeptidase A (MC-CPA) type that are stored in complex with serglycin, a proteoglycan with heparin side chains. Hence, serglycin-protease complexes are released upon MC degranulation and may influence local inflammation. Here we explored the possibility that a serglycin-protease axis may regulate levels of IL-13, a cytokine involved in allergic asthma. Indeed, we found that wild-type MCs efficiently degraded exogenous or endogenously produced IL-13 upon degranulation, whereas serglycin(-/-) MCs completely lacked this ability. Moreover, MC-mediated IL-13 degradation was blocked both by a serine protease inhibitor and by a heparin antagonist, which suggests that IL-13 degradation is catalyzed by serglycin-dependent serine proteases and that optimal IL-13 degradation is dependent on both the serglycin and the protease component of the serglycin-protease complex. Moreover, IL-13 degradation was abrogated in MC-CPA(-/-) MC cultures, but was normal in cultures of MCs with an inactivating mutation of MC-CPA, which suggests that the IL-13-degrading serine proteases rely on MC-CPA protein. Together, our data implicate a serglycin-serine protease axis in the regulation of extracellular levels of IL-13. Reduction of IL-13 levels through this mechanism possibly can provide a protective function in the context of allergic inflammation.
36.	Wennmalm, Stefan, et al. (författare) UV-Fluorescence Correlation Spectroscopy of 2-Aminopurine 2001 Ingår i: Biological chemistry (Print). - 1431-6730 .- 1437-4315. ; 382:3, s. 393-397 Tidskriftsartikel (refereegranskat)abstract We have built a fluorescence correlation spectroscopy (FCS) microscope for ultraviolet excitation (280 300 nm) and emission. With UV excitation the fluorescence of natural fluorophores such as the modified nucleotide 2-aminopurine can be analyzed. The sensitivity of a natural fluorophore toward conformational changes can reveal dynamics in biomolecules. UVFCS is well suited for detection of intensity fluctuations related to such conformational dynamics. Here we show UVFCS measured on pQuarterphenyl and on 2-aminopurine (2-AP). The triplet state rate constants and the excitation cross section for 2- AP were estimated to k[23]=1 x 10[6] s[-1], k[31]=3 x 10[5] s[-1], and σ=2 x 10[-17] cm[2].
37.	Wilhelmsson, Ulrika, 1970, et al. (författare) The role of GFAP and vimentin in learning and memory 2019 Ingår i: Biological Chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 400:9, s. 1147-1156 Tidskriftsartikel (refereegranskat)abstract Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles in cellular responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins of astrocytes, is the hallmark of astrocyte activation and reactive gliosis in response to injury, ischemia or neurodegeneration. Reactive gliosis is essential for the protective role of astrocytes at acute stages of neurotrauma or ischemic stroke. However, GFAP and Vim were also linked to neural plasticity and regenerative responses in healthy and injured brain. Mice deficient for GFAP and vimentin (GFAP(-/-)Vim(-/-)) exhibit increased post-traumatic synaptic plasticity and increased basal and post-traumatic hippocampal neurogenesis. Here we assessed the locomotor and exploratory behavior of GFAP(-/-)Vim(-/-) mice, their learning, memory and memory extinction, by using the open field, object recognition and Morris water maze tests, trace fear conditioning, and by recording reversal learning in IntelliCages. While the locomotion, exploratory behavior and learning of GFAP(-/-)Vim(-/-) mice, as assessed by object recognition, the Morris water maze, and trace fear conditioning tests, were comparable to wildtype mice, GFAP(-/-)Vim(-/-) mice showed more pronounced memory extinction when tested in IntelliCages, a finding compatible with the scenario of an increased rate of reorganization of the hippocampal circuitry.
38.	Wilhelmsson, Ulrika, 1970, et al. (författare) Vimentin is required for normal accumulation of body fat 2019 Ingår i: Biological Chemistry. - : Walter de Gruyter GmbH. - 1431-6730 .- 1437-4315. ; 400:9, s. 1157-1162 Tidskriftsartikel (refereegranskat)abstract Intermediate filaments (nanofilaments) have many functions, especially in response to cellular stress. Mice lacking vimentin (Vim -/- ) display phenotypes reflecting reduced levels of cell activation and ability to counteract stress, e.g. decreased reactivity of astrocytes after neurotrauma, decreased migration of astrocytes and fibroblasts, attenuated inflammation and fibrosis in lung injury, delayed wound healing, impaired vascular adaptation to nephrectomy, impaired transendothelial migration of lymphocytes, and attenuated atherosclerosis. To address the role of vimentin in fat accumulation, we assessed the body weight and fat by dual-energy X-ray absorptiometry (DEXA) in Vim -/- and matched wildtype mice. While the weight of 1.5 month old Vim -/- and wildtype mice was comparable, Vim -/- mice showed decreased body weight at 3.5, 5.5 and 8.5 months (males by 19-22%, females by 18-29%). At 8.5 months, Vim -/- males and females had less body fat compared to wildtype mice (a decrease by 24%, p<0.05, and 33%, p<0.0001, respectively). The body mass index in 8.5 months old Vim -/- mice was lower in males (6.8 vs 7.8, p<0.005) and females (6.0 vs 7.7, p<0.0001) despite the slightly lower body length of Vim -/- mice. Increased mortality was observed in adult Vim -/- males. We conclude that vimentin is required for normal accumulation of body fat. © 2019 by Walter de Gruyter Berlin/Boston 2019.
39.	Akoachere, Monique, et al. (författare) Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts. 2005 Ingår i: Biol Chem. - 1431-6730. ; 386:1, s. 41-52 Tidskriftsartikel (refereegranskat)abstract The glyoxalase system consisting of glyoxalase I (GloI) and glyoxalase II (GloII) constitutes a glutathione-dependent intracellular pathway converting toxic 2-oxoaldehydes, such as methylglyoxal, to the corresponding 2-hydroxyacids. Here we describe a complete glyoxalase system in the malarial parasite Plasmodium falciparum. The biochemical, kinetic and structural properties of cytosolic GloI (cGloI) and two GloIIs (cytosolic GloII named cGloII, and tGloII preceded by a targeting sequence) were directly compared with the respective isofunctional host enzymes. cGloI and cGloII exhibit lower K(m) values and higher catalytic efficiencies (k(cat)/K(m) ) than the human counterparts, pointing to the importance of the system in malarial parasites. A Tyr185Phe mutant of cGloII shows a 2.5-fold increase in K(m) , proving the contribution of Tyr185 to substrate binding. Molecular models suggest very similar active sites/metal binding sites of parasite and host cell enzymes. However, a fourth protein, which has highest similarities to GloI, was found to be unique for malarial parasites; it is likely to act in the apicoplast, and has as yet undefined substrate specificity. Various S-(N-hydroxy-N-arylcarbamoyl)glutathiones tested as P. falciparum Glo inhibitors were active in the lower nanomolar range. The Glo system of Plasmodium will be further evaluated as a target for the development of antimalarial drugs.
40.	Asakura, Y, et al. (författare) DNA-plasmids of HIV-1 induce systemic and mucosal immune responses 1999 Ingår i: Biological chemistry. - 1431-6730. ; 380:3, s. 375-379 Tidskriftsartikel (refereegranskat)
41.	Bengtson, Sara, et al. (författare) Regulation of kinin B(2) receptors by bradykinin in human lung cells. 2008 Ingår i: Biological Chemistry. - 1437-4315. ; 389, s. 1435-1440 Tidskriftsartikel (refereegranskat)abstract Abstract Bradykinin is a potent mediator of inflammation that has been shown to participate in allergic airway inflammation. The biologic effects of bradykinin are mediated by binding and activating its cognate receptor, the B(2) receptor (B(2)R). In the lung fibroblast cell line IMR-90, binding of bradykinin to the B(2)R triggers down-regulation of the receptor surface expression, suggesting that bradykinin-induced inflammation is transient and self-limited. Notably, subjects with chronic airway inflammation continue to respond to BK following a first challenge. B(2)Rs are expressed on many different lung cell types, including airway epithelial cells. We therefore compared IMR-90 cells with the human lung epithelial cell line BEAS2B and found that B2R expression in the two cell types is differently regulated by BK. While BK induces a down-regulation of B(2)R in IMR-90 cells, the same treatment leads to an up-regulation of the receptor in BEAS2B cells. These results provide a possible explanation for the potency of bradykinin in inducing ongoing airway inflammation.
42.	Berg, U, et al. (författare) Calpain proteolysis of insulin-like growth factor binding protein (IGFBP) -2 and -3, but not of IGFBP-1 2007 Ingår i: Biological chemistry. - 1431-6730. ; 388:8, s. 859-863 Tidskriftsartikel (refereegranskat)
43.	Bhushan, Shashi, et al. (författare) Proteolytic mechanism of a novel mitochondrial and chloroplastic PreP peptidasome. 2006 Ingår i: Biol Chem. - 1431-6730. ; 387:8, s. 1087-90 Tidskriftsartikel (refereegranskat)abstract The 2.1-A-resolution crystal structure of the novel mitochondrial and chloroplastic metalloendopeptidase, AtPreP1, revealed a unique peptidasome structure, in which the two halves of the enzyme completely enfold a huge proteolytic cavity. Based on the structure, we proposed a novel mechanism for proteolysis involving hinge-bending motions, which cause the protease to open and close in response to substrate binding. We generated four double-mutants of AtPreP1 by introducing cysteines at positions where disulfide bonds can be formed in order to lock and unlock the protease and tested the activity under oxidizing and reducing conditions. The overall results support the proposed mechanism.
44.	Blaukat, Andree, et al. (författare) Activation of sphingosine kinase by the bradykinin B2 receptor and its implication in regulation of the ERK/MAP kinase pathway. 2001 Ingår i: Biol Chem. - 1431-6730. ; 382:1, s. 135-9 Tidskriftsartikel (refereegranskat)abstract Sphingosine kinase phosphorylates sphingosine to generate sphingosine 1-phosphate, a phospholipid that has been implicated in signaling by a number of transmembrane receptors and was recently shown to act as a ligand for a specific class of G protein-coupled receptors. Here we show that the G protein-coupled bradykinin B2 receptor activates sphingosine kinase leading to a time- and dose-dependent elevation of cellular sphingosine 1-phosphate levels that was blocked by the sphingosine kinase inhibitor dihydrosphingosine. Furthermore, increasing doses of this inhibitor partially affected the bradykinin-mediated ERK/MAP kinase activation and fully blocked the protein kinase C-independent component of the signaling pathway from the B2 receptor to the ERK/MAP kinase cascade. Overexpression of sphingosine kinase did not additionally increase the bradykinin-induced ERK/MAP kinase activity, indicating a permissive rather than activating role of sphingosine 1-phosphate in B2 receptor-mediated mitogenic signaling.
45.	Bode, JG, et al. (författare) Hepatitis C virus (HCV) employs multiple strategies to subvert the host innate antiviral response 2008 Ingår i: Biological chemistry. - 1431-6730. ; 389:10, s. 1283-1298 Tidskriftsartikel (refereegranskat)
46.	Bode, JG, et al. (författare) Interplay between host cell and hepatitis C virus in regulating viral replication 2009 Ingår i: Biological chemistry. - 1437-4315. ; 390:10, s. 1013-1032 Tidskriftsartikel (refereegranskat)
47.	Bruning, J, et al. (författare) Highlight: The biology of aging: mechanisms and intervention 2010 Ingår i: Biological chemistry. - 1437-4315. ; 391:10, s. 1113-1113 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
48.	de Kruijff, Ben, et al. (författare) Striated domain self-organizing ordered assemblies of transmembrane α-helical peptides and lipids in bilayers 2006 Ingår i: Biological Chemistry. - 1437-4315. ; 387:3, s. 235-241 Tidskriftsartikel (refereegranskat)abstract This review summarizes the knowledge on striated domains, which are ordered assemblies of transmembrane peptides and lipids under gel-state conditions. The structure, mechanism of function and utility of this system as a model for domain formation is described, resulting in a molecular description of the domains and a discussion on the relevance of these insights for the function/formation and structure of similar domains in biological membranes.
49.	Diamandis, EP, et al. (författare) The First International Symposium on Kallikreins 2006 Ingår i: Biological Chemistry. - 1437-4315. ; 387:6, s. 635-636 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
50.	Edalat, M, et al. (författare) Selective recognition of peptide sequences by glutathione transferases: a possible mechanism for modulation of cellular stress-induced signaling pathways 2003 Ingår i: Biological chemistry. - 1431-6730. ; 384, s. 645-651 Tidskriftsartikel (refereegranskat)

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