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  • 1.
    Andersson, Håkan S.
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Figueredo, Sharel M.
    Haugaard-Kedström, Linda M.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Bengtsson, Elina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Daly, Norelle L.
    Qu, Xiaoqing
    Craik, David J.
    Ouellette, Andre J.
    Rosengren, K. Johan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    The alpha-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance2012Ingår i: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 43, nr 4, s. 1471-1483Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Andersson, Håkan S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jacobsson, Erik
    Uppsala University.
    Eriksson, Camilla
    Uppsala University.
    Hedström, Martin
    Lund University.
    Seth, Henrik
    University of Gothenburg.
    Sundberg, Per
    University of Gothenburg.
    Rosengren, K. Johan
    University of Queensland.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    The toxicity of ribbon worms: alpha-nemertides or tetrodotoxin, or both?2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82, nr Supplement 1, artikel-id P549Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The marine ribbon worms (nemerteans) are predators which capture their prey by everting a proboscis carrying a mixture of toxins which brings on rapid paralysis [1]. Moreover, ribbon worms have a thick layer of epidermal mucus of similar constitution. Tetrodotoxin (TTX) has been identified as one of these toxins [2]. The extreme toxicity of TTX (lethal by ingestion of 0.5-2 mg) is due to its ability to block voltage-gated sodium channels. Although several bacterial species (among these Vibrio sp.) have been linked to its synthesis, the biogenic origin and biosynthesis is unclear. One hypothesis is that TTX production occurs in a symbiotic relationship with its host, in this case the ribbon worm [3]. We have made significant effort to identify TTX in a setup for production through the cultivation of Vibrio alginolyticus in nutrient broth infused with mucus from the ribbon worm Lineus longissimus. Toxicity was demonstrated by fraction injections into shore crabs, but no TTX was found, and it could be shown conclusively that toxicity was unrelated to TTX and the Vibrio culture itself, and rather a constituent of the ribbon worm mucus [4]. The following studies led us to the discovery of a new class of peptides, the alpha-nemertides, in the mucus of the ribbon worms, which could be directly linked to the toxic effects. A literature review of the available evidence for TTX in ribbon worms show that the evidence in most cases are indirect, although notable exceptions exist. This points to the necessity to further investigate the presence and roles of TTX and alpha-nemertides in ribbon worms.

  • 3.
    Andersson, Håkan S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala university.
    Jacobsson, Erik
    Uppsala University.
    Laborde, Quentin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Rosengren, K. Johan
    University of Queensland, Australia.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    Alpha-nemertides - a novel family of nemertean peptide neurotoxins2018Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    We recently discovered a novel family of neuroactive peptides in nemerteans, which we have named alpha-nemertides (1). One of these peptides, nemertide alpha-1, has been the subject of detailed studies with regard to structure and effects. The peptide exhibits exceptional potency against a number of arthropod species. Moreover, in vitro experiments suggest that alpha-1 acts primarily on voltage-gated sodium channels, and that this action is selective for arthropods by two orders of magnitude over vertebrate species. Using transcriptomic and proteomic approaches, we have identified 10 alpha-nemertides, but this number is likely to increase. These peptides alongside with a series of mutants are currently under evaluation by our group, with the goal to improve our understanding of structure-function relationships. In addition, we are considering potential practical uses of alpha-nemertides. In this talk, I will describe the current status of this research project.

    1. E. Jacobsson et al., Peptide ion channel toxins from the bootlace worm, the longest animal on Earth. Scientific reports 8, 4596 (2018).

  • 4.
    Andersson, Håkan S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jacobsson, Erik
    Uppsala University.
    Rosengren, K. Johan
    University of Queensland, Australia.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    Discovery of novel ion-channel active peptide toxins in a North Sea Ribbon Worm2016Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Ribbon worms (nemerteans) are marine predators, which capture their prey using a proboscis containing a mixture of toxins which brings on rapid paralysis [1]. In addition, their epidermis contains thick mucus of similar toxic constitution. One very potent toxin reported in ribbon worm mucus is tetrodotoxin (TTX). However, despite significant efforts, Strand et al. [2] were unable to detect any TTX, neither in the mucus of the ribbon worm Lineus longissimus, nor from Vibrio alginolyticus cultures isolated from and cultivated in the mucus. These observations challenged the notion of general presence of TTX in ribbon worm mucus, and prompted us to look for other toxins [3]. Using LC-MS analysis of mucus extracts, we identified three peptides present in significant amounts. The peptides were sequenced using a combination of MS/MS analysis and transcriptomics, and whereas one of them strongly resembles the only peptide toxin previously characterized from ribbon worms, Neurotoxin B-IV [4], the other two were found to represent a previously unknown class of peptide toxins. The most abundant of these was synthesized, and its 3D structure determined. Preliminary toxicity tests on shore crab (C. maenas) indicated toxicity (through paralysis) on par with that of TTX. Further analyses have indicated that its toxic effects are due to binding to voltage sensitive sodium channels.

     

    With L. longissimus as our primary target, we are now mapping the presence of peptide toxins in ribbon worms, with the objectives to establish routes for synthesis, and to characterize the biological activities and structures of these peptides. The number of peptides of this novel class is increasing, and synthesis and characterization is well underway. The striking potencies of these peptides make them potentially amenable as novel insecticidal or anthelmintic leads, pharmacological tools or in biotechnology applications.

     

    References

    1. Strand M, Sundberg P. Nationalnyckeln till Sveriges flora och fauna [DO-DP]. Stjärnmaskar-Slemmaskar: Sipuncula-Nemertea: Artdatabanken, SLU; 2010.

    2. Strand M, Hedstrom M, Seth H, McEvoy EG, Jacobsson E, Goransson U, Andersson HS, Sundberg P. The Bacterial (Vibrio alginolyticus) Production of Tetrodotoxin in the Ribbon Worm Lineus longissimus-Just a False Positive? Marine Drugs. 2016;14(4).

    3. Strand M, Andersson HS. Slemmaskens hemlighet. Forskning & Framsteg. 2016;(2):26-33.

    4. Blumenthal KM, Kem WR. Structure and action of heteronemertine polypeptide toxins. Primary structure of Cerebratulus lacteus toxin B-IV. The Journal of Biological Chemistry. 1976;251(19):6025-9.

  • 5.
    Andersson, Håkan S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jacobsson, Erik
    Uppsala University.
    Rosengren, K. Johan
    University of Queensland, Australia.
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Göransson, Ulf
    Uppsala University.
    Mapping the diversity of nemertean peptide toxins2018Konferensbidrag (Övrigt vetenskapligt)
  • 6.
    Andersson, Håkan S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jacobsson, Erik
    Uppsala University.
    Strand, Malin
    Swedish agricultural university (SLU).
    Peigneur, Steve
    University of Leuven (KU Leuven), Belgium.
    Lebbe, Eline
    University of Leuven (KU Leuven), Belgium.
    Rosengren, K. Johan
    University of Queensland.
    Tytgat, Jan
    University of Leuven (KU Leuven), Belgium.
    Göransson, Ulf
    Uppsala University.
    Alpha-nemertides, a novel family of marine peptide neurotoxins from ribbon worms2017Konferensbidrag (Övrigt vetenskapligt)
  • 7.
    Bergman, Ingrid-Maria
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Edman, Kjell
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV. Uppsala University.
    Rosengren, K. Johan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV. The University of Queensland, Australia.
    Edfors, Inger
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Extensive polymorphism in the porcine Toll-like receptor 10 gene2012Ingår i: International Journal of Immunogenetics, ISSN 1744-3121, E-ISSN 1744-313X, Vol. 39, nr 1, s. 68-76Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    Bergman, Ingrid-Maria
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Edman, Kjell
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Rosengren, K. Johan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Edfors, Inger
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR)1, TLR2, TLR6, and TLR10 genes.2010Ingår i: International Symposium on Animal Genomics for Animal Health Paris, France, 31 May – 2 June 2010: The AGAH 2010 Abstract Book, 2010, s. 35-Konferensbidrag (Övrigt vetenskapligt)
    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. 

  • 9.
    Bergman, Ingrid-Maria
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Rosengren, K. Johan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Edman, Kjell
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Edfors, Inger
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    European wild boars and domestic pigs display different polymorphic patterns in the Toll-like receptor (TLR) 1, TLR2, and TLR6 genes2010Ingår i: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 62, nr 1, s. 49-58Artikel i tidskrift (Refereegranskat)
    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.

  • 10. Chen, Bin
    et al.
    Colgrave, Michelle
    Daly, Norelle
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Gustafson, Kirk
    Craik, David
    Isolation and characterization of novel cyclotides from Viola hederaceae - Solution structure and anti-HIV activity of vhl-1, a leaf-specific expressed cyclotide2005Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, nr 23, s. 22395-405Artikel i tidskrift (Refereegranskat)
  • 11. Clark, Richard
    et al.
    Fisher, Harold
    Dempster, Louise
    Daly, Norelle
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Nevin, Simon
    Meunier, Fred
    Adams, David
    Craik, David
    Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the alpha-conotoxin MII2005Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr 39, s. 13767-72Artikel i tidskrift (Refereegranskat)
  • 12. Craik, David
    et al.
    Daly, Norelle
    Colgrave, Michelle
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Discovery and applications of the cyclotides: circular proteins from plants2003Ingår i: Peptide Revolution: Genomics, Proteomics & Therapeutics / [ed] M. Chorev and T. Sawyer, Boston, USA, 2003Konferensbidrag (Refereegranskat)
  • 13.
    Craik, David
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia .
    Daly, Norelle
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia .
    Saska, Ivana
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia .
    Trabi, Manuela
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia .
    Rosengren, Johan
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia .
    Structures of naturally occurring circular proteins from bacteria2003Ingår i: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 185, nr 14, s. 4011-21Artikel, forskningsöversikt (Övrigt vetenskapligt)
  • 14.
    Daly, Norelle
    et al.
    University of Queensland, Australia.
    Chen, Yi
    University of Queensland, Australia.
    Rosengren, K. Johan
    University of Queensland, Australia.
    Marx, Ute
    University of Queensland, Australia.
    Phillips, Martin
    UCLA, USA.
    Waring, Alan
    UCLA, USA.
    Wang, Wei
    UCLA, USA.
    Lehrer, Robert
    UCLA, USA.
    Craik, David
    University of Queensland, Australia.
    Retrocyclin-2: a potent anti-HIV theta-defensin that forms a cyclic cysteine ladder structural motif2009Ingår i: Peptides for Youth: The Proceedings of the 20th American Peptide Symposium / [ed] Valle S.D., Escher E., Lubell W.D., Springer, 2009, Vol. 611, nr 11, s. 577-578Konferensbidrag (Refereegranskat)
  • 15. Daly, Norelle L.
    et al.
    Chen, Yi-Kuang
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Marx, Ute C.
    Phillips, Martin L.
    Waring, Alan J.
    Wang, Wei
    Lehrer, Robert I.
    Craik, David J.
    Retrocyclin-2: structural analysis of a potent anti-HIV theta-defensin2007Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, nr 35, s. 9920-8Artikel i tidskrift (Refereegranskat)
  • 16.
    Daly, Norelle
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia.
    Rosengren, K. Johan
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia.
    Craik, David
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072 Australia.
    Discovery, structure and biological activities of cyclotides2009Ingår i: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 61, s. 918-930Artikel, forskningsöversikt (Övrigt vetenskapligt)
    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.

  • 17. Göransson, Ulf
    et al.
    Herrmann, Anders
    Burman, Robert
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Rosengren, K. Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    The conserved Glu in the cyclotide cycloviolacin O2 has a key structural role2009Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, nr 14, s. 2354-2360Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are a large family of plant peptides that are characterised by a head-to-tail circular backbone and three disulfide bonds that are arranged in a cystine knot. This unique structural feature, which is referred to as a cyclic cystine knot, gives the cyclotides remarkable stability against chemical and biological degradation. In addition to their natural function as insecticides for plant defence, the cyclotides have a range of bioactivities with pharmaceutical relevance, including cytotoxicity against cancer cell lines. A glutamic acid residue, aside from the invariable disulfide array, is the most conserved feature throughout the cyclotide family, and it has recently been shown to be crucial for biological activity. Here we have used solution-state NMR spectroscopy to determine the three-dimensional structures of the potent cytotoxic cyclotide cycloviolacin O2, and an inactive analogue in which this conserved glutamic acid has been methylated. The structures of the peptides show that the glutamic acid has a key structural role in coordinating a set of hydrogen bonds in native cycloviolacin O2; this interaction is disrupted in the methylated analogue. The proposed mechanism of action of cyclotides is membrane disruption and these results suggest that the glutamic acid is linked to cyclotide function by stabilising the structure to allow efficient aggregation in membranes, rather than in a direct interaction with a target receptor.

  • 18.
    Haugaard-Kedström, Linda M.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Univ Queensland, Australia.
    Hossain, Mohammed Akhter
    Univ Melbourne, Australia.
    Daly, Norelle L
    Univ Queensland, Australia.
    Bathgate, Ross A D
    Univ Melbourne, Australia.
    Rinderknecht, Ernst
    Novartis Corp, USA.
    Wade, John D
    Univ Melbourne, Australia.
    Craik, David J
    Univ Queensland, Australia.
    Rosengren, K. Johan
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Univ Queensland, Australia.
    Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2.2015Ingår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, nr 3, s. 891-900Artikel i tidskrift (Refereegranskat)
    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.

  • 19.
    Haugaard-Kedström, Linda M.
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Shabanpoor, Fazel
    Florey Neuroscience, The University of Melbourne.
    Hossain, Mohammed Akhter
    Florey Neuroscience, The University of Melbourne.
    Clark, Richard
    The University of Queensland, Institute for Molecular Bioscience .
    Ryan, Philip
    Florey Neuroscience, The University of Melbourne.
    Craik, David
    The University of Queensland, Institute for Molecular Bioscience .
    Gundlach, Andrew
    Florey Neuroscience, The University of Melbourne.
    Wade, John
    Florey Neuroscience, The University of Melbourne.
    Bathgate, Ross
    Florey Neuroscience, The University of Melbourne.
    Rosengren, K. Johan
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP32011Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, nr 13, s. 4965-4974Artikel i tidskrift (Refereegranskat)
  • 20.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hossain, Akther
    Daly, Norelle
    Bathgate, Ross
    Craik, David
    Wade, John
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Structural characterization of a H3-INSL5 relaxin peptide chimera2007Ingår i: Proceedings of the 4th International Peptide Symposium / [ed] Wilce, Jackie, Cairns, Australia, 2007Konferensbidrag (Refereegranskat)
  • 21.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hossain, M. Akhter
    Daly, Norelle L.
    Bathgate, Ross A.D.
    Wade, John D.
    Craik, David J.
    Rosengren, K. Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Structural Properties of Relaxin Chimeras: NMR Characterization of the R3/I5 Relaxin Peptide2009Ingår i: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1160, s. 27-30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Relaxin-3 interacts with high potency with three relaxin family peptide receptors (RXFP1, RXFP3, and RXFP4). Therefore, the development of selective agonist and antagonist analogs is important for in vivo studies characterizing the biological significance of the different receptor-ligand systems and for future pharmaceutical applications. Recent reports demonstrated that a peptide selective for RXFP3 and RXFP4 over RXFP1 can be generated by the combination of the relaxin-3 B chain with the A chain from insulin-like peptide 5 (INSL5), creating an R3/I5 chimera. We have used NMR spectroscopy to determine the three-dimensional structure of this peptide to gain structural insights into the consequences of combining chains from two different relaxins. The R3/I5 structure reveals a similar backbone conformation for the relaxin-3 B chain compared to native relaxin-3, and the INSL5 A chain displays a relaxin/insulin-like fold with two parallel helices. The findings indicate that binding and activation of RXFP3 and RXFP4 mainly require the B chain and that the A chain functions as structural support. RXFP1, however, demonstrates a more complex binding mechanism, involving both the A chain and the B chain. The creation of chimeras is a promising strategy for generating new structure-activity data on relaxins.

  • 22.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hossain, M. Akhter
    Daly, Norelle L.
    Craik, David J.
    Wade, John D.
    Rosengren, K. Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Structure of the human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework2009Ingår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 419, s. 619-627Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INSL5 (insulin-like peptide 5) is a two-chain peptide hormone related to insulin and relaxin. It was recently discovered through searches of expressed sequence tag databases and, although the fulfil biological significance of INSL5 is still being elucidated, high expression in peripheral tissues such as the colon, as well as in the brain and hypothalamus, suggests roles in gut contractility and neuroendocrine signalling. INSL5 activates the relaxin family peptide receptor 4 with high potency and appears to be the endogenous ligand for this receptor, on the basis of overlapping expression profiles and their apparent co-evolution. In the present Study, we have used solution-state NMR to characterize the three-dimensional structure of synthetic human INSL5. The structure reveals an insulin/relaxin-like fold with three helical segments that are braced by three disulfide bonds and enclose a hydrophobic core. Furthermore, we characterized in detail the hydrogen-bond network and electrostatic interactions between charged groups in INSL5 by NMR-monitored temperature and pH titrations and Undertook a comprehensive structural comparison with other members of the relaxin family, thus identifying the conserved structural features of the relaxin fold. The B-chain helix, which is the primary receptor-binding site of the relaxins, is longer in INSL5 than in its close relative relaxin-3. As this feature results in a different positioning of the receptor-activation domain Arg(B23) and Trp(B24), it may be an important contributor to the difference in biological activity observed for these two peptides. Overall, the structural Studies provide mechanistic insights into the receptor selectivity of this important family of hormones. 

  • 23.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hossain, Mohammed Akhter
    Daly, Norelle L.
    Bathgate, Ross A.D.
    Wade, John D.
    Craik, David J.
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist2008Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 35, s. 23811-23818Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human relaxin family comprises seven peptide hormones with various biological functions mediated through interactions with G-protein-coupled receptors. Interestingly, among the hitherto characterized receptors there is no absolute selectivity toward their primary ligand. The most striking example of this is the relaxin family ancestor, relaxin-3, which is an agonist for three of the four currently known relaxin receptors: GPCR135, GPCR142, and LGR7. Relaxin-3 and its endogenous receptor GPCR135 are both expressed predominantly in the brain and have been linked to regulation of stress and feeding. However, to fully understand the role of relaxin-3 in neurological signaling, the development of selective GPCR135 agonists and antagonists for in vivo studies is crucial. Recent reports have demonstrated that such selective ligands can be achieved by making chimeric peptides comprising the relaxin-3 B-chain combined with the INSL5 A-chain. To obtain structural insights into the consequences of combining A-and B-chains from different relaxins we have determined the NMR solution structure of a human relaxin-3/INSL5 chimeric peptide. The structure reveals that the INSL5 A-chain adopts a conformation similar to the relaxin-3 A-chain, and thus has the ability to structurally support a native-like conformation of the relaxin-3 B-chain. These findings suggest that the decrease in activity at the LGR7 receptor seen for this peptide is a result of the removal of a secondary LGR7 binding site present in the relaxin-3 A-chain, rather than conformational changes in the primary B-chain receptor binding site. 

  • 24.
    Helin, Anu S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Aarts, Lauren
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Bususu, Isaya
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Andersson, Håkan S.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Rosengren, K. Johan
    University of Queensland, Australia‎.
    Chapman, Joanne R.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM). University of Kansas, USA.
    Waldenström, Jonas
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Antimicrobial activity differences in reduced vs. oxidized AvBD3b peptides in mallards (Anas platyrhynchos).2017Konferensbidrag (Övrigt vetenskapligt)
  • 25.
    Helin, Anu S.
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Aarts, Lauren
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Bususu, Isaya
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Andersson, Håkan S.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Rosengren, K. Johan
    University of Queensland, Australia.
    Chapman, Joanne R.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Waldenström, Jonas
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Antimicrobial differences between AvBDs in mallards (Anas platyrhynchos)2018Konferensbidrag (Övrigt vetenskapligt)
  • 26. Hossain, M. Akhter
    et al.
    Bathgate, Ross A.D.
    Kong, Chze K.R.
    Shabanpoor, Fazel
    Zhang, Suode
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Tregear, Geoffrey W.
    Wade, John D.
    Synthesis, conformation, and activity of human insulin-like peptide 5 (INSL5)2008Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, nr 11, s. 1816-1822Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Insulin-like peptide 5 (INSL5) was first identified through searches of the expressed sequence tags (EST) databases. Primary sequence analysis showed it to be a prepropeptide that was predicted to be processed in vivo to yield a two-chain sequence (A and B) that contained the insulin-like disulfide cross-links. The high affinity interaction between INSL5 and the receptor RXFP4 (GPCR142) coupled with their apparent coevolution and partially overlapping tissue expression patterns strongly suggest that INSL5 is an endogenous ligand for RXFP4. Given that the primary function of the INSL5–RXFP4 pair remains unknown, an effective means of producing sufficient quantities of this peptide and its analogues is needed to systematically investigate its structural and biological properties. A combination of solid-phase peptide synthesis methods together with regioselective disulfide bond formation were used to obtain INSL5. Both chains were unusually resistant to standard synthesis protocols and required highly optimized conditions for their acquisition. In particular, the use of a strong tertiary amidine, DBU, as Nα-deprotection base was required for the successful assembly of the B chain; this highlights the need to consider incomplete deprotection rather than acylation as a cause of failed synthesis. Following sequential disulfide bond formation and chain combination, the resulting synthetic INSL5, which was obtained in good overall yield, was shown to possess a similar secondary structure to human relaxin-3 (H3 relaxin). The peptide was able to inhibit cAMP activity in SK-N-MC cells that expressed the human RXFP4 receptor with a similar activity to H3 relaxin. In contrast, it had no activity on the human RXFP3 receptor. Synthetic INSL5 demonstrates equivalent activity to the recombinant-derived peptide, and will be an important tool for the determination of its biological function.

  • 27. Hossain, M. Akhter
    et al.
    Bathgate, Ross A.D.
    Rosengren, K. Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Shabanpoor, Fazel
    Zhang, Suode
    Lin, Feng
    Tregear, Geoffrey W.
    Wade, John D.
    The structural and functional role of the B-chain C-terminal arginine in the relaxin-3 peptide antagonist, R3(B Delta 23-27)R/I5.2009Ingår i: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 73, nr 1, s. 46-52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Relaxin-3, a member of the insulin superfamily, is involved in regulating stress and feeding behavior. It is highly expressed in the brain and is the endogenous ligand for the receptor RXFP3. As relaxin-3 also interacts with the relaxin receptor RXFP1, selective agonists and antagonists are crucial for studying the physiological function(s) of the relaxin-3/RXFP3 pair. The analog R3(B Delta 23-27)R/I5, in which a C-terminally truncated human relaxin-3 (H3) B-chain is combined with the INSL5 A-chain, is a potent selective RXFP3 antagonist and has an Arg residue remaining on the B-chain C-terminus as a consequence of the recombinant protein production process. To investigate the role of this residue in the RXFP3 receptor binding and activation, the analogs R3(B Delta 23-27)R/I5 and R3(B Delta 23-27)R containing the B-chain C-terminal Arg as well as R3(B Delta 23-27)/I5 and R3(B Delta 23-27), both lacking the Arg, were chemically assembled and their secondary structure and receptor activity assessed. The peptides generally had a similar conformation but those with the extra Arg residue displayed a significantly increased affinity for the RXFP3. Interestingly, in contrast to R3(B Delta 23-27)R and R3(B Delta 23-27)R/I5, the peptide R3(B Delta 23-27) is a weak agonist. This suggests that the C-terminal Arg, although increasing the affinity, alters the manner in which the peptide binds to the receptor and thereby prevents activation, giving R3(B Delta 23-27)R/I5 its potent antagonistic activity.

  • 28. Hossain, M. Akhter
    et al.
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Zhang, Suode
    Layfield, Sharon
    Ferraro, Tania
    Daly, Norelle L.
    Tregear, Geoffrey W.
    Wade, John D.
    Bathgate, Ross A.D.
    The A-chain of the human relaxin family peptides has distinct roles in the binding and activation of the different relaxin family peptide receptors2008Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 25, s. 17287-17297Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The relaxin peptides are a family of hormones that share a structural fold characterized by two chains, A and B, that are cross-braced by three disulfide bonds. Relaxins signal through two different classes of G-protein-coupled receptors (GPCRs), leucine-rich repeat-containing GPCRs LGR7 and LGR8 together with GPCR135 and GPCR142, now referred to as the relaxin family peptide (RXFP) receptors 1-4, respectively. Although key binding residues have been identified in the B-chain of the relaxin peptides, the role of the A-chain in their activity is currently unknown. A recent study showed that INSL3 can be truncated at the N terminus of its A-chain by up to 9 residues without affecting the binding affinity to its receptor RXFP2 while becoming a high affinity antagonist. This suggests that the N terminus of the INSL3 A-chain contains residues essential for RXFP2 activation. In this study, we have synthesized A-chain truncated human relaxin-2 and -3 (H2 and H3) relaxin peptides, characterized their structure by both CD and NMR spectroscopy, and tested their binding and cAMP activities on RXFP1, RXFP2, and RXFP3. In stark contrast to INSL3, A-chain-truncated H2 relaxin peptides lost RXFP1 and RXFP2 binding affinity and concurrently cAMP-stimulatory activity. H3 relaxin A-chain-truncated peptides displayed similar properties on RXFP1, highlighting a similar binding mechanism for H2 and H3 relaxin. In contrast, A-chain-truncated H3 relaxin peptides showed identical activity on RXFP3, highlighting that the B-chain is the sole determinant of the H3 relaxin-RXFP3 interaction. Our results provide new insights into the action of relaxins and demonstrate that the role of the A-chain for relaxin activity is both peptide- and receptor-dependent. 

  • 29. Hossain, M. Akhter
    et al.
    Rosengren, K. Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Zhang, Suode
    Bathgate, Ross A.D.
    Tregear, Geoffrey W.
    van Lierop, Bianca J.
    Robinson, Andrea J.
    Wade, John D.
    Solid phase synthesis and structural analysis of novel A-chain dicarba analogs of human relaxin-3 (INSL7) that exhibit full biological activity2009Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 7, nr 8, s. 1547-1553Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Replacement of disulfide bonds with non-reducible isosteres can be a useful means of increasing the in vivo stability of a protein. We describe the replacement of the A-chain intramolecular disulfide bond of human relaxin-3 (H3 relaxin, INSL7), an insulin-like peptide that has potential applications in the treatment of stress and obesity, with the physiologically stable dicarba bond. Solid phase peptide synthesis was used to prepare an A-chain analogue in which the two cysteine residues that form the intramolecular bond were replaced with allylglycine. On-resin microwave-mediated ring closing metathesis was then employed to generate the dicarba bridge. Subsequent cleavage of the peptide from the solid support, purification of two isomers and their combination with the B-chain via two intermolecular disulfide bonds, then furnished two isomers of dicarba-H3 relaxin. These were characterized by CD spectroscopy, which suggested a structural similarity to the native peptide. Additional analysis by solution NMR spectroscopy also identified the likely cis/trans form of the analogs. Both peptides demonstrated binding affinities that were equivalent to native H3 relaxin on RXFP1 and RXFP3 expressing cells. However, although the cAMP activity of the analogs on RXFP3 expressing cells was similar to the native peptide, the potency on RXFP1 expressing cells was slightly lower. The data confirmed the use of a dicarba bond as a useful isosteric replacement of the disulfide bond.

  • 30.
    Jacobsson, Erik
    et al.
    Uppsala University.
    Andersson, Håkan S.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Strand, Malin
    Swedish University of Agricultural Sciences.
    Lebbe, Eline
    University of Leuven (KU Leuven), Belgium.
    Eriksson, Camilla
    Uppsala University.
    Peigneur, Steve
    University of Leuven (KU Leuven), Belgium.
    Rosengren, K. Johan
    University of Queensland, Australia.
    Tytgat, Jan
    University of Leuven (KU Leuven), Belgium.
    Göransson, Ulf
    Uppsala University.
    Peptide toxins from the longest animal on earth.2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82, nr Supplement 1, artikel-id YRW3Artikel i tidskrift (Övrigt vetenskapligt)
  • 31.
    Jacobsson, Erik
    et al.
    Uppsala University, Sweden.
    Andersson, Håkan S.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Strand, Malin
    Swedish University of Agricultural Sciences, Sweden.
    Peigneur, Steve
    Univ Leuven, Belgium.
    Eriksson, Camilla
    Uppsala University, Sweden.
    Loden, Henrik
    Uppsala University, Sweden.
    Shariatgorji, Mohammadreza
    Uppsala University, Sweden.
    Andren, Per E.
    Uppsala University, Sweden.
    Lebbe, Eline K. M.
    Univ Leuven, Belgium.
    Rosengren, K. Johan
    Univ Queensland, Australia.
    Tytgat, Jan
    Univ Leuven, Belgium.
    Göransson, Ulf
    Uppsala University, Sweden.
    Peptide ion channel toxins from the bootlace worm, the longest animal on Earth2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 4596Artikel i tidskrift (Refereegranskat)
    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.

  • 32. Jennings, C V
    et al.
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Daly, N L
    Plan, M
    Stevens, J
    Scanlon, M J
    Waine, C
    Norman, D G
    Anderson, M A
    Craik, D J
    Isolation, solution structure, and insecticidal activity of Kalata B2, a circular protein with a twist: Do Mobius strips exist in nature?2005Ingår i: Biochemistry, Vol. 44, nr 3, s. 851-60Artikel i tidskrift (Refereegranskat)
  • 33. Korsinczky, Michael
    et al.
    Schirra, Horst
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    West, Jenny
    Condie, Barry
    Otvos, Laszlo
    Anderson, Marilyn
    Craik, David
    Solution structures by H-1 NMR of the novel cyclic trypsin inhibitor SFTI-1 from sunflower seeds and an acyclic permutant2001Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 311, nr 3, s. 579-91Artikel i tidskrift (Refereegranskat)
  • 34. Maemoto, Atsu
    et al.
    Qu, Xiaqing
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Tanabe, Hiroki
    Henschen-Edman, Agnes
    Craik, David
    Ouellette, Andre
    Functional analysis of the alpha-defensin disulfide array in mouse cryptdin-42004Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 279, nr 42, s. 44188-96Artikel i tidskrift (Refereegranskat)
  • 35.
    Månsson, Alf
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Balaz, Martina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Torres, Nuria Albet
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Rosengren, Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    In vitro assays of molecular motors - impact of motor-surface interactions2008Ingår i: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 13, nr May 1, s. 5732-5754Artikel, forskningsöversikt (Övrigt vetenskapligt)
    Abstract [en]

    In many types of biophysical studies of both single molecules and ensembles of molecular motors the motors are adsorbed to artificial surfaces. Some of the most important assay systems of this type (in vitro motility assays and related single molecule techniques) will be briefly described together with an account of breakthroughs in the understanding of actomyosin function that have resulted from their use. A poorly characterized, but potentially important, entity in these studies is the mechanism of motor adsorption to surfaces and the effects of motor surface interactions on experimental results. A better understanding of these phenomena is also important for the development of commercially viable nanotechnological applications powered by molecular motors. Here, we will consider several aspects of motor surface interactions with a particular focus on heavy meromyosin (HMM) from skeletal muscle. These aspects will be related to heavy meromyosin structure and relevant parts of the vast literature on protein-surface interactions for non-motor proteins. An overview of methods for studying motor-surface interactions will also be given. The information is used as a basis for further development of a model for HMM-surface interactions and is discussed in relation to experiments where nanopatterning has been employed for in vitro reconstruction of actomyosin order. The challenges and potentials of this approach in biophysical studies, compared to the use of self-assembly of biological components into supramolecular protein aggregates (e. g. myosin filaments) will be considered. Finally, this review will consider the implications for further developments of motor-powered lab-on-a-chip devices.

  • 36.
    Nicholls, Ian A.
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Andersson, Håkan S.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Charlton, Christy
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Henschel, Henning
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Karlsson, Björn C. G.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Karlsson, Jesper G.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    O'Mahony, John
    Rosengren, Annika M.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Rosengren, K. Johan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Wikman, Susanne
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Theoretical and Computational Strategies for Rational Molecularly Imprinted Polymer Design2009Ingår i: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 25, nr 3, s. 543-552Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The further evolution of molecularly imprinted polymer science and technology necessitates the development of robust predictive tools capable of handling the complexity of molecular imprinting systems. A combination of the rapid growth in computer power over the past decade and significant software developments have opened new possibilities for simulating aspects of the complex molecular imprinting process. We present here a survey of the current status of the use of in silico-based approaches to aspects of molecular imprinting. Finally, we highlight areas where ongoing and future efforts should yield information critical to our understanding of the underlying mechanisms sufficient to permit the rational design of molecularly imprinted polymers. 

  • 37.
    Plan, Manuel R
    et al.
    Univ Queensland, Div Chem & Struct Biol, Inst Mol Biosci, St Lucia, Qld 4067 Australia.
    Rosengren, K. Johan
    Univ Queensland, Div Chem & Struct Biol, Inst Mol Biosci, St Lucia, Qld 4067 Australia.
    Sando, Lillian
    Univ Queensland, Div Chem & Struct Biol, Inst Mol Biosci, St Lucia, Qld 4067 Australia.
    Daly, Norelle L
    Univ Queensland, Div Chem & Struct Biol, Inst Mol Biosci, St Lucia, Qld 4067 Australia.
    Craik, David J
    Univ Queensland, Div Chem & Struct Biol, Inst Mol Biosci, St Lucia, Qld 4067 Australia.
    Structural and biochemical characteristics of the cyclotide kalata B5 from Oldenlandia affinis.2010Ingår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 94, nr 5, Sp. Iss. SI, s. 647-658Artikel i tidskrift (Refereegranskat)
    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.

  • 38.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Bathgate, Ross
    Craik, David
    Daly, Norelle
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hossain, Akther
    Lin, Feng
    Wade, John
    Structural insights into the action of relaxin peptide hormones2007Ingår i: Proceedings of the 4th International Peptide Symposium / [ed] Wilce, Jackie, Cairns, Australia, 2007Konferensbidrag (Refereegranskat)
  • 39.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Blond, Alain
    Afonson, Carlos
    Tabet, Jean Claude
    Rebuffat, Sylvie
    Craik, David
    Structure of thermolysin cleaved microcin J25: Extreme stability of a two-chain antimicrobial peptide devoid of covalent links2004Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 43, nr 16, s. 4696-702Artikel i tidskrift (Refereegranskat)
  • 40.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Clark, Richard
    Daly, Norelle
    Göransson, Ulf
    Jones, Alun
    Craik, David
    Microcin J25 has a threaded sidechain-to-backbone ring structure and not a head-to-tail cyclized backbone2003Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 125, nr 41, s. 12464-74Artikel i tidskrift (Refereegranskat)
  • 41.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Daly, N L
    Fornander, L M
    Haugaard-Kedström (published under the name Jönsson), Linda M.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Shirafuji, Y
    Qu, X Q
    Vogel, H J
    Ouellette, A J
    Craik, D J
    Structural and functional characterization of the conserved salt bridge in mammalian Paneth cell alpha-defensins - Solution structures of mouse cryptdin-4 AND (E15D)-cryptdin-42006Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, nr 38, s. 28068-28078Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    alpha-Defensins are mediators of mammalian innate immunity, and knowledge of their structure-function relationships is essential for understanding their mechanisms of action. We report here the NMR solution structures of the mouse Paneth cell alpha-defensin cryptdin-4 (Crp4) and a mutant (E15D)-Crp4 peptide, in which a conserved Glu(15) residue was replaced by Asp. Structural analysis of the two peptides confirms the involvement of this Glu in a conserved salt bridge that is removed in the mutant because of the shortened side chain. Despite disruption of this structural feature, the peptide variant retains a well defined native fold because of a rearrangement of side chains, which result in compensating favorable interactions. Furthermore, salt bridge-deficient Crp4 mutants were tested for bactericidal effects and resistance to proteolytic degradation, and all of the variants had similar bactericidal activities and stability to proteolysis. These findings support the conclusion that the function of the conserved salt bridge in Crp4 is not linked to bactericidal activity or proteolytic stability of the mature peptide.

  • 42.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Daly, Norelle
    Plan, Manuel
    Wayne, Clement
    Craik, David
    Twists, knots, and rings in proteins - Structural definition of the cyclotide framework2003Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, nr 10, s. 8606-16Artikel i tidskrift (Refereegranskat)
  • 43.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Daly, Norelle
    Scanlon, Martin
    Craik, David
    Solution structure of BSTI: A new trypsin inhibitor from skin secretions of Bombina bombina2001Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 40, nr 15, s. 4601-09Artikel i tidskrift (Refereegranskat)
  • 44.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Göransson, Ulf
    Otvos, Laszlo
    Craik, David
    Cyclization of pyrrhocoricin retains structural elements crucial for the antimicrobial activity of the native peptide2004Ingår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 76, nr 5, s. 446-58Artikel i tidskrift (Refereegranskat)
  • 45.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Jen, Freda
    Clark, Richard
    Daly, Norelle
    Göransson, Ulf
    Jones, Alun
    Craik, David
    A novel threaded ring structure for the antimicrobial peptide microcin J252004Ingår i: Proceedings of the 28th European Peptide Symposium, Prague, Chech Republique, 2004Konferensbidrag (Refereegranskat)
  • 46.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Kragol, Goran
    Hoffmann, Ralph
    Chattergoon, Michael
    Lovas, Sandor
    Cudic, Marie
    Bulet, Phil
    Condie, Barry
    Montaner, Louis
    Otvos, Laszlo
    Identification of crucial residues for the antibacterial activity of the proline-rich peptide, pyrrhocoricin2002Ingår i: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 269, nr 17, s. 4226-37Artikel i tidskrift (Refereegranskat)
  • 47.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Lin, F
    Bathgate, R A D
    Tregear, G W
    Daly, N L
    Wade, J D
    Craik, D J
    Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-32006Ingår i: Journal of Biological chemistry, Vol. 281, nr 9, s. 5845-5851Artikel i tidskrift (Refereegranskat)
  • 48.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    McManus, Ailsa
    Craik, David
    The structural and functional diversity of naturally occurring antimicrobial peptides2002Ingår i: Current Medicinal Chemistry - Anti Infective Agents, Vol. 1, nr 4, s. 319-341Artikel, forskningsöversikt (Övrigt vetenskapligt)
    Abstract [en]

    Antimicrobial peptides occur in a diverse range of organisms from microorganisms to insects, plants and animals. Although they all have the common function of inhibiting or killing invading microorganisms they achieve this function using an extremely diverse range of structural motifs. Their sizes range from approximately 10-90 amino acids. Most carry an overall positive charge, reflecting a preferred mode of electrostatic interaction with negatively charged microbial membranes. This article describes the structural diversity of a representative set of antimicrobial peptides divided into five structural classes: those with -helical structure, those with -sheet structure, those with mixed helical / - sheet structure, those with irregular structure, and those incorporating a macrocyclic structure. There is a significant diversity in both the size and charge of molecules within each of these classes and between the classes. The common feature of their three-dimensional structures is, however, that they have a degree of amphipathic character in which there is separate localisation of hydrophobic regions and positively charged regions. An emerging trend amongst antimicrobial proteins is the discovery of more macrocyclic analogues. Cyclisation appears to impart an additional degree of stability on these molecules and minimizes proteolytic cleavage. In conclusion, there appear to be a number of promising opportunities for the development of novel clinically useful antimicrobial peptides based on knowledge of the structures of naturally occurring antimicrobial molecules.

  • 49.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Wilson, David
    Daly, Norelle
    Alewood, Paul
    Craik, David
    Solution structures of the cis- and trans-Pro30 isomers of a novel 38-residue toxin from the venom of Hadronyche infensa sp that contains a cystine-knot motif within its four disulfide bonds2002Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 41, nr 10, s. 3394-401Artikel i tidskrift (Refereegranskat)
  • 50.
    Rosengren, Johan
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Zhang, S
    Lin, F
    Daly, N L
    Scott, D J
    Hughes, R A
    Bathgate, R A D
    Craik, D J
    Wade, J D
    Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 32006Ingår i: Journal of biological chemistry, Vol. 281, nr 38, s. 28287-28295Artikel i tidskrift (Refereegranskat)
12 1 - 50 av 57
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