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Rosengren, K. Johan
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Publications (10 of 49) Show all publications
Jacobsson, E., Andersson, H. S., Strand, M., Peigneur, S., Eriksson, C., Loden, H., . . . Göransson, U. (2018). Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Scientific Reports, 8, Article ID 4596.
Open this publication in new window or tab >>Peptide ion channel toxins from the bootlace worm, the longest animal on Earth
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4596Article in journal (Refereed) Published
Abstract [en]

Polypeptides from animal venoms have found important uses as drugs, pharmacological tools, and within biotechnological and agricultural applications. We here report a novel family of cystine knot peptides from nemertean worms, with potent activity on voltage-gated sodium channels. These toxins, named the alpha-nemertides, were discovered in the epidermal mucus of Lineus longissimus, the 'bootlace worm' known as the longest animal on earth. The most abundant peptide, the 31-residue long alpha-1, was isolated, synthesized, and its 3D NMR structure determined. Transcriptome analysis including 17 species revealed eight alpha-nemertides, mainly distributed in the genus Lineus. alpha-1 caused paralysis and death in green crabs (Carcinus maenas) at 1 mu g/kg (similar to 300 pmol/kg). It showed profound effect on invertebrate voltage-gated sodium channels (e.g. Blattella germanica Na(v)1) at low nanomolar concentrations. Strong selectivity for insect over human sodium channels indicates that a-nemertides can be promising candidates for development of bioinsecticidal agents.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
Keywords
ribbon worms, nemertea, peptide toxin, sodium channel, insecticide
National Category
Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-72295 (URN)10.1038/s41598-018-22305-w (DOI)000428029600001 ()29567943 (PubMedID)
Funder
Swedish Research Council, 2014-3327
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-06-26Bibliographically approved
Haugaard-Kedström, L. M., Hossain, M. A., Daly, N. L., Bathgate, R. A., Rinderknecht, E., Wade, J. D., . . . Rosengren, K. J. (2015). Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2.. ACS Chemical Biology, 10(3), 891-900
Open this publication in new window or tab >>Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2.
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2015 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, no 3, p. 891-900Article in journal (Refereed) Published
Abstract [en]

Relaxin is a member of the relaxin/insulin peptide hormone superfamily and is characterized by a two-chain structure constrained by three disulfide bonds. Relaxin is a pleiotropic hormone and involved in a number of physiological and pathogenic processes, including collagen and cardiovascular regulation and tissue remodelling during pregnancy and cancer. Crystallographic and ultracentrifugation experiments have revealed that the human form of relaxin, H2 relaxin, self-associates into dimers, but the significance of this is poorly understood. Here, we present the NMR structure of a monomeric, amidated form of H2 relaxin and compare its features and behavior in solution to those of native H2 relaxin. The overall structure of H2 relaxin is retained in the monomeric form. H2 relaxin amide is fully active at the relaxin receptor RXFP1 and thus dimerization is not required for biological activity. Analysis of NMR chemical shifts and relaxation parameters identified internal motion in H2 relaxin at the pico-nanosecond and milli-microsecond time scales, which is commonly seen in other relaxin and insulin peptides and might be related to function.

National Category
Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-39719 (URN)10.1021/cb500918v (DOI)000351558700028 ()25547165 (PubMedID)2-s2.0-84925365962 (Scopus ID)
Available from: 2015-02-04 Created: 2015-02-04 Last updated: 2017-12-05Bibliographically approved
Bergman, I.-M., Edman, K., Nilsson Ekdahl, K., Rosengren, K. J. & Edfors, I. (2012). Extensive polymorphism in the porcine Toll-like receptor 10 gene. International Journal of Immunogenetics, 39(1), 68-76
Open this publication in new window or tab >>Extensive polymorphism in the porcine Toll-like receptor 10 gene
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2012 (English)In: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 39, no 1, p. 68-76Article in journal (Refereed) Published
Abstract [en]

The great importance of the Toll-like receptors (TLRs) in innate immunity is well established, but one family member – TLR10 – remains elusive. TLR10 is expressed in various tissues in several species, but its ligand is not known and its function is still poorly understood. The open reading frame of TLR10 was sequenced in 15 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace and Large White origin. Amino acid positions corresponding to detected nonsynonymous single nucleotide polymorphisms (SNPs) were analysed in the crystal structures determined for the human TLR1–TLR2–lipopeptide complex and the human TLR10 Toll/Interleukin 1 receptor (TIR) dimer. SNP occurrence in wild boars and domestic pigs was compared, and haplotypes for the TLR10 gene and the TLR6-1-10 gene cluster were reconstructed. Despite the limited number of animals sequenced in the present study (N = 30), a larger number of SNPs were found in TLR10 than recently reported for TLR1, TLR6 and TLR2. Thirty-three SNPs were detected, of which 20 were nonsynonymous. The relative frequency of nonsynonymous (dN) and synonymous (dS) SNPs between wild boars and domestic pigs was higher in TLR10 than recently reported for TLR1, TLR6 and TLR2. However, the polymorphism reported in the present study seems to leave the function of the TLR10 molecule unaffected. Furthermore, no nonsynonymous SNPs were detected in the part of the gene corresponding to the hinge region of the receptor, probably reflecting rigorously acting functional constraint. The total number of SNPs and the number of nonsynonymous SNPs were significantly lower (< 0.05) in the wild boars than in the domestic pigs, and fewer TLR10 haplotypes were present in the wild boars. The majority of the TLR6-1-10 haplotypes were specific for either wild boars or domestic pigs, probably reflecting differences in microbial environment and population history.

National Category
Immunology Genetics
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-15033 (URN)10.1111/j.1744-313X.2011.01057.x (DOI)2-s2.0-84855348173 (Scopus ID)
Available from: 2011-10-19 Created: 2011-10-19 Last updated: 2017-12-08Bibliographically approved
Andersson, H. S., Figueredo, S. M., Haugaard-Kedström, L. M., Bengtsson, E., Daly, N. L., Qu, X., . . . Rosengren, K. J. (2012). The alpha-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance. Amino Acids, 43(4), 1471-1483
Open this publication in new window or tab >>The alpha-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance
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2012 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 43, no 4, p. 1471-1483Article in journal (Refereed) Published
Abstract [en]

Salt-bridge interactions between acidic and basic amino acids contribute to the structural stability of proteins and to protein-protein interactions. A conserved salt-bridge is a canonical feature of the alpha-defensin antimicrobial peptide family, but the role of this common structural element has not been fully elucidated. We have investigated mouse Paneth cell alpha-defensin cryptdin-4 (Crp4) and peptide variants with mutations at Arg(7) or Glu(15) residue positions to disrupt the salt-bridge and assess the consequences on Crp4 structure, function, and stability. NMR analyses showed that both (R7G)-Crp4 and (E15G)-Crp4 adopt native-like structures, evidence of fold plasticity that allows peptides to reshuffle side chains and stabilize the structure in the absence of the salt-bridge. In contrast, introduction of a large hydrophobic side chain at position 15, as in (E15L)-Crp4 cannot be accommodated in the context of the Crp4 primary structure. Regardless of which side of the salt-bridge was mutated, salt-bridge variants retained bactericidal peptide activity with differential microbicidal effects against certain bacterial cell targets, confirming that the salt-bridge does not determine bactericidal activity per se. The increased structural flexibility induced by salt-bridge disruption enhanced peptide sensitivity to proteolysis. Although sensitivity to proteolysis by MMP7 was unaffected by most Arg(7) and Glu(15) substitutions, every salt-bridge variant was degraded extensively by trypsin. Moreover, the salt-bridge facilitates adoption of the characteristic alpha-defensin fold as shown by the impaired in vitro refolding of (E15D)-proCrp4, the most conservative salt-bridge disrupting replacement. In Crp4, therefore, the canonical alpha-defensin salt-bridge facilitates adoption of the characteristic alpha-defensin fold, which decreases structural flexibility and confers resistance to degradation by proteinases.

Keywords
Defensin, Cryptdin-4, Crp4, Salt-bridge, Structure, Folding, Proteolytic stability
National Category
Organic Chemistry
Research subject
Chemistry, Biochemistry; Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-22288 (URN)10.1007/s00726-012-1220-3 (DOI)000309070700007 ()2-s2.0-84867577474 (Scopus ID)
Available from: 2012-11-06 Created: 2012-11-06 Last updated: 2017-04-18Bibliographically approved
Haugaard-Kedström, L. M., Shabanpoor, F., Hossain, M. A., Clark, R., Ryan, P., Craik, D., . . . Rosengren, K. J. (2011). Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP3. Journal of the American Chemical Society, 133(13), 4965-4974
Open this publication in new window or tab >>Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP3
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2011 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, no 13, p. 4965-4974Article in journal (Refereed) Published
National Category
Chemical Sciences
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-9785 (URN)10.1021/ja110567j (DOI)2-s2.0-79953858024 (Scopus ID)
Available from: 2010-12-21 Created: 2010-12-20 Last updated: 2017-04-19Bibliographically approved
Bergman, I.-M., Rosengren, K. J., Edman, K. & Edfors, I. (2010). European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR) 1, TLR2, and TLR6 genes. Immunogenetics, 62(1), 49-58
Open this publication in new window or tab >>European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR) 1, TLR2, and TLR6 genes
2010 (English)In: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 62, no 1, p. 49-58Article in journal (Refereed) Published
Abstract [en]

During the last decade, the Toll-like receptors (TLRs) have been extensively studied and their immense importance in innate immunity is now being unveiled. Here, we report pronounced differences – probably reflecting the domestication process and differences in selective pressure – between wild boars and domestic pigs regarding single nucleotide polymorphisms (SNPs) in TLR genes. The open reading frames of TLR1, TLR2, and TLR6 were sequenced in 25 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace, and Large White origin. In total, 20, 27, and 26 SNPs were detected in TLR1, TLR2, and TLR6, respectively. In TLR1 and TLR2, the numbers of SNPs detected were significantly lower (P ≤ 0.05, P ≤ 0.01) in the wild boars than in the domestic pigs. In the wild boars, one major high frequency haplotype was found in all three genes, while the same pattern was exhibited only by TLR2 in the domestic pigs. The relative frequency of non-synonymous (dN) and synonymous (dS) SNPs was lower for the wild boars than for the domestic pigs in all three genes. In addition, differences in diversity between the genes were revealed: the mean heterozygosity at the polymorphic positions was markedly lower in TLR2 than in TLR1 and TLR6. Because of its localization – in proximity of the bound ligand – one of the non-synonymous SNPs detected in TLR6 may represent species-specific function on the protein level. Furthermore, the codon usage pattern in the genes studied deviated from the general codon usage pattern in Sus scrofa.

Place, publisher, year, edition, pages
Springer, 2010
Keywords
polymorphism, Toll-like receptor (TLR), selection, swine, codon usage
National Category
Genetics
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-107 (URN)10.1007/s00251-009-0409-4 (DOI)
Available from: 2010-03-17 Created: 2010-03-17 Last updated: 2017-12-12Bibliographically approved
Bergman, I.-M., Edman, K., Rosengren, K. J. & Edfors, I. (2010). European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR)1, TLR2, TLR6, and TLR10 genes.. In: International Symposium on Animal Genomics for Animal Health Paris, France, 31 May – 2 June 2010: The AGAH 2010 Abstract Book. Paper presented at International Symposium on Animal Genomics for Animal Heallth, Paris, 31 maj-2 juni, 2010 (pp. 35).
Open this publication in new window or tab >>European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR)1, TLR2, TLR6, and TLR10 genes.
2010 (English)In: International Symposium on Animal Genomics for Animal Health Paris, France, 31 May – 2 June 2010: The AGAH 2010 Abstract Book, 2010, p. 35-Conference paper, Published paper (Other academic)
Abstract [en]

The Toll-like receptors (TLR) are vitally important pattern recognition receptors linking innate and adaptive immunity. Several single nucleotide polymorphisms (SNP) in human TLR genes have been associated with disease. There are few studies on associations between polymorphisms in TLR genes and disease in pigs, but the TLR2/TLR6 heterodimer is activated by Mycoplasma hyopneumoniae, and the expression of TLR2, TLR4, and TLR9 is modulated in the presence of different Salmonella serovars. Porcine TLR1, TLR6, and TLR10 are located in a cluster on the p arm of chromosome 8, while TLR2 resides on the q arm. Previously, we identified quantitative trait loci (QTL) for immune-related traits on pig chromosome 8, close to the KIT gene and the microsatellite S0225, respectively. In order to explore polymorphism in some TLR genes in European wild boars and domestic pigs, TLR1, TLR2, and TLR6 were sequenced in 25 wild boars, representing three populations, and in 15 domestic pigs of Hampshire, Landrace, and Large White origin. Similarly, TLR10 was sequenced in 15 wild boars and 15 domestic pigs. In TLR1 and TLR2, more SNP were present in the domestic pigs than in the wild boars. In TLR6, SNP numbers were similar in both animal groups, but the level of heterozygosity was higher in the domestic pigs than in the wild boars. In TLR10, again, more SNP were present in the domestic pigs, and a higher number of nonsynonymous SNP were detected in TLR10 compared to the other genes. This may suggest redundancy for TLR10 in pigs. 

National Category
Genetics Medical Bioscience
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-7426 (URN)
Conference
International Symposium on Animal Genomics for Animal Heallth, Paris, 31 maj-2 juni, 2010
Available from: 2010-08-17 Created: 2010-08-17 Last updated: 2014-02-25Bibliographically approved
Plan, M. R., Rosengren, K. J., Sando, L., Daly, N. L. & Craik, D. J. (2010). Structural and biochemical characteristics of the cyclotide kalata B5 from Oldenlandia affinis.. Biopolymers, 94(5, Sp. Iss. SI), 647-658
Open this publication in new window or tab >>Structural and biochemical characteristics of the cyclotide kalata B5 from Oldenlandia affinis.
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2010 (English)In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 94, no 5, Sp. Iss. SI, p. 647-658Article in journal (Refereed) Published
Abstract [en]

Cyclotides are a large family of plant-derived proteins typified by their head-to-tail cyclic backbone and knotted arrangement of three disulfide bonds. Although they display a diverse range of biological activities, their native function is thought to be plant defense. Here we characterized the expression, three-dimensional structure, and hemolytic activity of the cyclotide kalata B5 from the African plant Oldenlandia affinis. Kalata B5 shows an interesting seasonal variation in its expression and can only be isolated during certain times of the year, when the plant is flowering. It displays a typical tightly folded cyclic cystine knot structure. A range of pH and temperature titrations reveal that a conserved glutamic acid in loop 1 of the structure forms a key hydrogen bond network, similar to that reported previously for other cyclotides. However, specific line broadening in the NMR spectra of kalata B5 suggests that the hydrogen bonding network in this peptide is less rigid than in other cyclotides. Notably, the pK(a) of Glu6 of 4.5 is higher than the values for other cyclotides studied so far, which range from 3.0 to 4.0, providing a further indication of a weaker hydrogen bond network. Kalata B5 has only moderate hemolytic activity compared with other highly expressed cyclotides, and this reduced activity probably reflects its more flexible structure. As is the case with other cyclotides, kalata B5 has an exposed hydrophobic region on its surface, supporting suggestions that this hydrophobic patch is a key feature for membrane binding and biological activity of cyclotides. (c) 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2010.

Identifiers
urn:nbn:se:lnu:diva-7753 (URN)10.1002/bip.21409 (DOI)20564013 (PubMedID)
Note

Symposium on Biopolymers Peptide Science held at Ist International Conference on Circular Proteins Queens Isl, AUSTRALIA, OCT, 2009

Available from: 2010-08-24 Created: 2010-08-24 Last updated: 2017-12-12Bibliographically approved
Wang, C., Hu, S.-H., Martin, J., Sjögren, T., Hajdu, J., Bohlin, L., . . . Craik, D. J. (2009). Combined X-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold. Journal of Biological Chemistry, 284(16), 10672-10683
Open this publication in new window or tab >>Combined X-ray and NMR analysis of the stability of the cyclotide cystine knot fold that underpins its insecticidal activity and potential use as a drug scaffold
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2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 16, p. 10672-10683Article in journal (Refereed) Published
Abstract [en]

Cyclotides are a family of plant defense proteins that are highly resistant to adverse chemical, thermal, and enzymatic treatment. Here, we present the first crystal structure of a cyclotide, varv F, from the European field pansy, Viola arvensis, determined at a resolution of 1.8 angstrom. The solution state NMR structure was also determined and, combined with measurements of biophysical parameters for several cyclotides, provided an insight into the structural features that account for the remarkable stability of the cyclotide family. The x-ray data confirm the cystine knot topology and the circular backbone, and delineate a conserved network of hydrogen bonds that contribute to the stability of the cyclotide fold. The structural role of a highly conserved Glu residue that has been shown to regulate cyclotide function was also determined, verifying its involvement in a stabilizing hydrogen bond network. We also demonstrate that varv F binds to dodecylphosphocholine micelles, defining the binding orientation and showing that its structure remains unchanged upon binding, further demonstrating that the cyclotide fold is rigid. This study provides a biological insight into the mechanism by which cyclotides maintain their native activity in the unfavorable environment of predator insect guts. It also provides a structural basis for explaining how a cluster of residues important for bioactivity may be involved in self-association interactions in membranes. As well as being important for their bioactivity, the structural rigidity of cyclotides makes them very suitable as a stable template for peptide-based drug design.

National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry; Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-2095 (URN)10.1074/jbc.M900021200 (DOI)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2017-12-12Bibliographically approved
Daly, N., Rosengren, K. J. & Craik, D. (2009). Discovery, structure and biological activities of cyclotides. Advanced Drug Delivery Reviews, 61, 918-930
Open this publication in new window or tab >>Discovery, structure and biological activities of cyclotides
2009 (English)In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 61, p. 918-930Article, review/survey (Other academic) Published
Abstract [en]

Cyclotides are small disulfide-rich peptides that are characterized by a head-to-tail cyclized peptide backbone and a knotted arrangement of three conserved disulfide bonds. They are present in many plants from the Violaceae, Rubiaceae and Cucurbitaceae families, with individual plants expressing a suite of dozens of cyclotides. So far > 140 sequences and 15 three-dimensional structures have been determined but it is estimated that the family probably comprises many thousands of members. Their primary function in plants is thought to be as defense agents, based on their potent insecticidal activity, but they also have a range of other biological activities, including anti-HIV, antimicrobial and cytotoxic activities. Because of their exceptional stability they have attracted interest as templates for protein engineering and drug design applications. This article gives an overview of the discovery of cyclotides, describes their unique structural features and range of bioactivities, and discusses their applications in drug design.

Place, publisher, year, edition, pages
Advanced Drug Delivery Reviews, 2009
National Category
Medicinal Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:hik:diva-2707 (URN)10.1016/j.addr.2009.05.003 (DOI)
Available from: 2009-10-16 Created: 2010-02-16 Last updated: 2018-01-12Bibliographically approved
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