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| 2. |
- Jacobsson, Erik, et al.
(author)
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Peptide ion channel toxins from the bootlace worm, the longest animal on Earth
- 2018
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
- Aboye, Teshome L., et al.
(author)
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A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity
- 2015
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In: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 16:7, s. 1068-1077
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Journal article (peer-reviewed)abstract
- Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.
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| 5. |
- Andersson, Håkan S., 1967-, et al.
(author)
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Alpha-nemertides - a novel family of nemertean peptide neurotoxins
- 2018
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Conference paper (other academic/artistic)abstract
- 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).
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| 6. |
- Andersson, Håkan S., 1967-, et al.
(author)
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Discovery of novel ion-channel active peptide toxins in a North Sea Ribbon Worm
- 2016
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Conference paper (other academic/artistic)abstract
- 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. References1. 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.
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| 9. |
- Andersson, Håkan S., 1967-, et al.
(author)
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The toxicity of ribbon worms: alpha-nemertides or tetrodotoxin, or both?
- 2016
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In: Planta Medica. - : Georg Thieme Verlag KG. - 0032-0943 .- 1439-0221. ; 82:Supplement 1
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Journal article (other academic/artistic)abstract
- 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.
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| 10. |
- Burman, Robert, et al.
(author)
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Distribution of circular proteins in plants : large-scale mapping of cyclotides in the Violaceae
- 2015
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In: Frontiers in Plant Science. - : Frontiers Media SA. - 1664-462X. ; 6
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Journal article (peer-reviewed)abstract
- During the last decade there has been increasing interest in small circular proteins found in plants of the violet family (Violaceae). These so-called cyclotides consist of a circular chain of approximately 30 amino acids, including six cysteines forming three disulfide bonds, arranged in a cyclic cystine knot (CCK) motif. In this study we map the occurrence and distribution of cyclotides throughout the Violaceae. Plant material was obtained from herbarium sheets containing samples up to 200 years of age. Even the oldest specimens contained cyclotides in the preserved leaves, with no degradation products observable, confirming their place as one of the most stable proteins in nature. Over 200 samples covering 17 of the 23-31 genera in Violaceae were analyzed, and cyclotides were positively identified in 150 species. Each species contained a unique set of between one and 25 cyclotides, with many exclusive to individual plant species. We estimate the number of different cyclotides in the Violaceae to be 5000-25,000, and propose that cyclotides are ubiquitous among all Violaceae species. Twelve new cyclotides from six phylogenetically dispersed genera were sequenced. Furthermore, the first glycosylated derivatives of cyclotides were identified and characterized, further increasing the diversity and complexity of this unique protein family.
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