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  • 1.
    Andersson, Håkan S.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Figueredo, Sharel M.
    Haugaard-Kedström, Linda M.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Bengtsson, Elina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Daly, Norelle L.
    Qu, Xiaoqing
    Craik, David J.
    Ouellette, Andre J.
    Rosengren, K. Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    The alpha-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance2012In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 43, no 4, p. 1471-1483Article in journal (Refereed)
    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. Göransson, Ulf
    et al.
    Herrmann, Anders
    Burman, Robert
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren, K. Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    The conserved Glu in the cyclotide cycloviolacin O2 has a key structural role2009In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, no 14, p. 2354-2360Article in journal (Refereed)
    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.

  • 3.
    Haugaard-Kedström, Linda M.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Structure and function of relaxins2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The relaxin/insulin superfamily is a group of peptide hormones that consists of ten members in human, namely relaxins 1-3, insulin-like peptides (INSL) 3-6, insulin and insulin-like growth factors (IGF) I-II. These peptides have various functions in the body, such as regulating growth, blood glucose levels,  collagen metabolism, germ cell maturation and appetite. Misregulation of these mechanisms is associated with disease and accordingly they are of interest as potential pharmaceutical targets. Structurally the hormones are characterised by two peptide chains, A and B, which are held together by one intra A-chain and two inter chain disulfide bonds. Four different G-protein coupled receptors (GPCR) called relaxin family peptide receptor (RXFP) 1-4 have been found to respond to stimuli by different relaxin peptides. RXFP3 and RXFP4 are classic peptide ligand GPCRs, whereas RXFP1 and RXFP2 are characterised by a large extracellular leucine rich-repeat domain. Relaxin-3, which is the relaxin family ancestor, is the only relaxin peptide known to be able to bind and activate both subtypes of GPCRs, namely RXFP1, RXFP3 and RXFP4.

    The aim of this thesis was to analyse the structure-function relationship of the relaxin ligands and receptors, and to use this information to develop selective ligands for the relaxin receptors, which can be used as drug leads or pharmacological tools for investigating the physiological roles of the RXFPs.

    The 3D structures of native INSL5 and relaxin-2 were determined by solution NMR spectroscopy. The peptides showed an insulin/relaxin-like overall fold. A relaxin chimera peptide, consisting of the A-chain from INSL5 and the B-chain from relaxin-3, R3/I5, which has been shown to be selective for RXFP3 and RXFP4 over RXFP1, was also subjected to NMR studies. The R3/I5 peptide maintained an insulin/relaxin-like overall fold, and the relaxin-3 B-chain adopted a conformation identical to that in native relaxin-3, confirming that the activity of R3/I5 can be directly related to its primary sequence. Furthermore, a truncation study was undertaken to ascertain the importance of the termini for structure and function. By using the knowledge generated from the structure-function relationship, a single-chain high affinity RXFP3 selective antagonist was developed.

    In conclusion, this thesis has contributed to broaden the knowledge of the structure-function relationship of the relaxin ligands and the development of a selective RXFP3 antagonist, which is currently a drug lead for treatment of neurological disorders including stress and obesity.

  • 4.
    Haugaard-Kedström, Linda M.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Hossain, Mohammed Akhter
    Florey Neuroscience, The University of Melbourne.
    Daly, Norelle
    University of Queensland, Institute for Molecular Bioscience.
    Bathgate, Ross
    Florey Neuroscience, The University of Melbourne.
    Rinderknecht, Ernst
    Corthera, c/o Norvartis Corporation.
    Wade, John
    Florey Neuroscience, The University of Melbourne.
    Craik, David
    The University of Queensland, Institute for Molecular Bioscience .
    Rosengren, Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Solution structure, aggregration behaviour and flexibility of human relaxin-2 - implications for biological functionManuscript (preprint) (Other academic)
  • 5.
    Haugaard-Kedström, Linda M.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. 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
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Queensland, Australia.
    Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2.2015In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 10, no 3, p. 891-900Article in journal (Refereed)
    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.

  • 6.
    Haugaard-Kedström, Linda M.
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    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
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP32011In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, no 13, p. 4965-4974Article in journal (Refereed)
  • 7.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hossain, Akther
    Daly, Norelle
    Bathgate, Ross
    Craik, David
    Wade, John
    Rosengren, Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Structural characterization of a H3-INSL5 relaxin peptide chimera2007In: Proceedings of the 4th International Peptide Symposium / [ed] Wilce, Jackie, Cairns, Australia, 2007Conference paper (Refereed)
  • 8.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hossain, M. Akhter
    Daly, Norelle L.
    Bathgate, Ross A.D.
    Wade, John D.
    Craik, David J.
    Rosengren, K. Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Structural Properties of Relaxin Chimeras: NMR Characterization of the R3/I5 Relaxin Peptide2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1160, p. 27-30Article in journal (Refereed)
    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.

  • 9.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hossain, M. Akhter
    Daly, Norelle L.
    Craik, David J.
    Wade, John D.
    Rosengren, K. Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Structure of the human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework2009In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 419, p. 619-627Article in journal (Refereed)
    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. 

  • 10.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hossain, Mohammed Akhter
    Daly, Norelle L.
    Bathgate, Ross A.D.
    Wade, John D.
    Craik, David J.
    Rosengren, Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist2008In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 35, p. 23811-23818Article in journal (Refereed)
    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. 

  • 11. 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.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren, Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Tregear, Geoffrey W.
    Wade, John D.
    Synthesis, conformation, and activity of human insulin-like peptide 5 (INSL5)2008In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 11, p. 1816-1822Article in journal (Refereed)
    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.

  • 12. Hossain, M. Akhter
    et al.
    Rosengren, Johan
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    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 receptors2008In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 25, p. 17287-17297Article in journal (Refereed)
    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. 

  • 13.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Johnson, Christina
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Fure, Hilde
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Landsem, Anne
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Haugaard-Kedström, Linda M.
    Univ Copenhagen, Denmark.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Brekke, Ole-Lars
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 136-137Article in journal (Other academic)
  • 14.
    Rosengren, Johan
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bathgate, Ross
    Craik, David
    Daly, Norelle
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hossain, Akther
    Lin, Feng
    Wade, John
    Structural insights into the action of relaxin peptide hormones2007In: Proceedings of the 4th International Peptide Symposium / [ed] Wilce, Jackie, Cairns, Australia, 2007Conference paper (Refereed)
  • 15.
    Rosengren, Johan
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Daly, N L
    Fornander, L M
    Haugaard-Kedström (published under the name Jönsson), Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    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-42006In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 38, p. 28068-28078Article in journal (Refereed)
    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.

  • 16.
    Rosengren, K. Johan
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bathgate, Ross A.D.
    Craik, David J.
    Daly, Norelle L.
    Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hossain, M. Akhter
    Wade, John D.
    Structural insights into the function of relaxins2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1160, p. 20-26Article in journal (Refereed)
    Abstract [en]

    The relaxin peptide hormones are members of the insulin superfamily and share a structural fold that is characterized by two peptide chains which are cross-braced by three disulfide bonds. On this framework, various amino acid side chains are presented, allowing specific interactions with different receptors. The relaxin receptors belong to two unrelated classes of G-protein-coupled receptors, but interestingly they are not selective for a single relaxin peptide. Relaxin-3, which is considered to be an extreme example of the relaxin family, can activate receptors from both classes and in fact interacts to some degree with all four receptors identified to date. To deduce how changes in the primary sequence can fine-tune the overall structure and thus the ability to interact with the various receptors, we have studied a range of relaxin-like peptides using solution nuclear magnetic resonance analysis. Three-dimensional structures of relaxin-3, insulin-like peptide 3 (INSL3), and INSL5 were determined and revealed a number of interesting features. All peptides showed a significant amount of line-broadening in certain regions, in particular around the intra-A-chain disulfide bond, suggesting that despite the disulfide bonds the fold is rather dynamic. Although the peptides share a common structural core there are significant differences, particularly around the termini. The structural data in combination with mutational studies provide valuable insights into the structure-activity relationships of relaxins.

  • 17.
    Rosengren, K. Johan
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences. University of Queensland.
    Haugaard Jönsson, Linda M.
    University of Kalmar, School of Pure and Applied Natural Sciences. University of Copenhagen.
    Bengtsson, Elina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Daly, Norelle
    University of Queensland.
    Fornander, Liselotte M
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Qu, Xiaoqing
    University of California.
    Tanabe, Hiroki
    University of California.
    Craik, David J
    University of Queensland.
    Ouellette, Andre J
    University of California.
    Structural and Functional Role of the Conserved Salt-Bridge in the Mammalian alpha-Defensin Cryptdin-4.2007Conference paper (Other academic)
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