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Studies of the biological properties of human beta-defensin 1.

Pazgier M, Prahl A, Hoover DM, Lubkowski J
J Biol Chem 282 1819-29 (2007)
Related entries: 2nlb, 2nlc, 2nld, 2nle, 2nlf, 2nlh, 2nlp, 2nlq, 2nls

Cited: 38 times
EuropePMC logo PMID: 17071614

Abstract

Defensins are small (30-45 amino acid residues) cationic proteins with broad antimicrobial activity against many bacteria and fungi, some enveloped viruses, and other activities such as chemoattraction of a range of different cell types to the sites of inflammation. These proteins represent attractive targets for developing novel antimicrobial agents and modulators of immune responses with therapeutic applicability. In this report, we present the results of functional and structural studies of 26 single-site mutants of human beta-defensin 1 (hBD1). All mutants were assayed for antimicrobial activity against Escherichia coli (ATCC strain 25922) and for chemotactic activity with CCR6-transfected HEK293 cells. To analyze the structural implications of mutagenesis and to verify the correctness of the disulfide connectivity, we used x-ray crystallography to conduct complete structural studies for 10 mutants in which the topology of disulfides was the same as in the native hBD1. Mutations did not induce significant changes of the tertiary structure, suggesting that the observed alterations of biological properties of the mutants were solely associated with changes in the respective side chains. We found that cationic residues located near the C terminus (Arg(29), Lys(31), Lys(33), and Lys(36)) of hBD1 define most of the anti-E. coli in vitro activity of this protein. In turn, nearly all mutations altering the CCR6-mediated chemotaxis are located at one area of the protein, defined by the N-terminal alpha-helical region (Asp(1)... Ser(8)) and a few topologically adjacent residues (Lys(22), Arg(29), and Lys(33)). These experimental results allow for the first time drafting of the CCR6-epitope for a defensin molecule.

Reviews citing this publication (5)

  1. Topical antimicrobials for burn wound infections. Dai T, Huang YY, Sharma SK, Hashmi JT, Kurup DB, Hamblin MR. Recent Pat Antiinfect Drug Discov 5 124-151 (2010)
  2. Peptides and Peptidomimetics for Antimicrobial Drug Design. Mojsoska B, Jenssen H. Pharmaceuticals (Basel) 8 366-415 (2015)
  3. Inflammatory bowel disease: an impaired barrier disease. Jäger S, Stange EF, Wehkamp J. Langenbecks Arch Surg 398 1-12 (2013)
  4. Structure-activity relationships in beta-defensin peptides. Taylor K, Barran PE, Dorin JR. Biopolymers 90 1-7 (2008)
  5. Defensins: antimicrobial peptides for therapeutic development. Verma C, Seebah S, Low SM, Zhou L, Liu SP, Li J, Beuerman RW. Biotechnol J 2 1353-1359 (2007)

Articles citing this publication (33)

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  2. Porcine beta-defensin 2 displays broad antimicrobial activity against pathogenic intestinal bacteria. Veldhuizen EJ, Rijnders M, Claassen EA, van Dijk A, Haagsman HP. Mol Immunol 45 386-394 (2008)
  3. Dimerization of plant defensin NaD1 enhances its antifungal activity. Lay FT, Mills GD, Poon IK, Cowieson NP, Kirby N, Baxter AA, van der Weerden NL, Dogovski C, Perugini MA, Anderson MA, Kvansakul M, Hulett MD. J Biol Chem 287 19961-19972 (2012)
  4. Directional and balancing selection in human beta-defensins. Hollox EJ, Armour JA. BMC Evol Biol 8 113 (2008)
  5. The antimicrobial activity of CCL28 is dependent on C-terminal positively-charged amino acids. Liu B, Wilson E. Eur J Immunol 40 186-196 (2010)
  6. A theoretical approach to spot active regions in antimicrobial proteins. Torrent M, Nogués VM, Boix E. BMC Bioinformatics 10 373 (2009)
  7. Antimicrobial peptide β-defensin-1 expression is upregulated in Alzheimer's brain. Williams WM, Torres S, Siedlak SL, Castellani RJ, Perry G, Smith MA, Zhu X. J Neuroinflammation 10 127 (2013)
  8. Molecular diversity of antimicrobial effectors in the oyster Crassostrea gigas. Schmitt P, Gueguen Y, Desmarais E, Bachère E, de Lorgeril J. BMC Evol Biol 10 23 (2010)
  9. A molecular dynamics study of human defensins HBD-1 and HNP-3 in water. Sharadadevi A, Nagaraj R. J Biomol Struct Dyn 27 541-550 (2010)
  10. Delineation of interfaces on human alpha-defensins critical for human adenovirus and human papillomavirus inhibition. Tenge VR, Gounder AP, Wiens ME, Lu W, Smith JG. PLoS Pathog 10 e1004360 (2014)
  11. Molecular and functional analysis of human β-defensin 3 action at melanocortin receptors. Nix MA, Kaelin CB, Ta T, Weis A, Morton GJ, Barsh GS, Millhauser GL. Chem Biol 20 784-795 (2013)
  12. Expression of Pla2g2a prevents carcinogenesis in Muc2-deficient mice. Fijneman RJ, Peham JR, van de Wiel MA, Meijer GA, Matise I, Velcich A, Cormier RT. Cancer Sci 99 2113-2119 (2008)
  13. FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6. Bhattacharyya S, Ghosh SK, Shokeen B, Eapan B, Lux R, Kiselar J, Nithianantham S, Young A, Pandiyan P, McCormick TS, Weinberg A. Infect Immun 84 1446-1456 (2016)
  14. Structure-function studies of chemokine-derived carboxy-terminal antimicrobial peptides. Nguyen LT, Chan DI, Boszhard L, Zaat SA, Vogel HJ. Biochim Biophys Acta 1798 1062-1072 (2010)
  15. Artificial beta-defensin based on a minimal defensin template. Antcheva N, Morgera F, Creatti L, Vaccari L, Pag U, Pacor S, Shai Y, Sahl HG, Tossi A. Biochem J 421 435-447 (2009)
  16. Importance of residue 13 and the C-terminus for the structure and activity of the antimicrobial peptide aurein 2.2. Cheng JT, Hale JD, Kindrachuk J, Jenssen H, Elliott M, Hancock RE, Straus SK. Biophys J 99 2926-2935 (2010)
  17. Sequence polymorphism and expression variability of Crassostrea gigas immune related genes discriminate two oyster lines contrasted in term of resistance to summer mortalities. Schmitt P, Santini A, Vergnes A, Degremont L, de Lorgeril J. PLoS One 8 e75900 (2013)
  18. Defensin-related peptide 1 (Defr1) is allelic to Defb8 and chemoattracts immature DC and CD4+ T cells independently of CCR6. Taylor K, Rolfe M, Reynolds N, Kilanowski F, Pathania U, Clarke D, Yang D, Oppenheim J, Samuel K, Howie S, Barran P, Macmillan D, Campopiano D, Dorin J. Eur J Immunol 39 1353-1360 (2009)
  19. Modification of β-Defensin-2 by Dicarbonyls Methylglyoxal and Glyoxal Inhibits Antibacterial and Chemotactic Function In Vitro. Kiselar JG, Wang X, Dubyak GR, El Sanadi C, Ghosh SK, Lundberg K, Williams WM. PLoS One 10 e0130533 (2015)
  20. The vaginal microbiota and innate immunity after local excisional treatment for cervical intraepithelial neoplasia. Mitra A, MacIntyre DA, Paraskevaidi M, Moscicki AB, Mahajan V, Smith A, Lee YS, Lyons D, Paraskevaidis E, Marchesi JR, Bennett PR, Kyrgiou M. Genome Med 13 176 (2021)
  21. Effects on antigen-presenting cells of short-term interaction with the human host defence peptide β-defensin 2. Morgera F, Pacor S, Creatti L, Antcheva N, Vaccari L, Tossi A. Biochem J 436 537-546 (2011)
  22. Interaction of antibacterial peptides spanning the carboxy-terminal region of human beta-defensins 1-3 with phospholipids at the air-water interface and inner membrane of E. coli. Krishnakumari V, Nagaraj R. Peptides 29 7-14 (2008)
  23. Peptide fragments of a beta-defensin derivative with potent bactericidal activity. Reynolds NL, De Cecco M, Taylor K, Stanton C, Kilanowski F, Kalapothakis J, Seo E, Uhrin D, Campopiano D, Govan J, Macmillan D, Barran P, Dorin JR. Antimicrob Agents Chemother 54 1922-1929 (2010)
  24. Streptococcus pyogenes infection of tonsil explants is associated with a human β-defensin 1 response from control but not recurrent acute tonsillitis patients. Bell S, Howard A, Wilson JA, Abbot EL, Smith WD, Townes CL, Hirst BH, Hall J. Mol Oral Microbiol 27 160-171 (2012)
  25. Prediction of the impact of coding missense and nonsense single nucleotide polymorphisms on HD5 and HBD1 antibacterial activity against Escherichia coli. Porto WF, Nolasco DO, Pires ÁS, Pereira RW, Franco OL, Alencar SA. Biopolymers 106 633-644 (2016)
  26. Human-β-defensins-1-3 and analogs do not require proton motive force for antibacterial activity against Escherichia coli. Krishnakumari V, Packiyanathan KK, Nagaraj R. FEMS Microbiol Lett 348 52-57 (2013)
  27. A peptide derived from human bactericidal/permeability-increasing protein (BPI) exerts bactericidal activity against Gram-negative bacterial isolates obtained from clinical cases of bovine mastitis. Chockalingam A, McKinney CE, Rinaldi M, Zarlenga DS, Bannerman DD. Vet Microbiol 125 80-90 (2007)
  28. Antimicrobial characterization of site-directed mutagenesis of porcine beta defensin 2. Huang XX, Gao CY, Zhao QJ, Li CL. PLoS One 10 e0118170 (2015)
  29. HD5 and HBD1 variants' solvation potential energy correlates with their antibacterial activity against Escherichia coli. Porto WF, Nolasco DO, Pires ÁS, Fernandes GR, Franco OL, Alencar SA. Biopolymers 106 43-50 (2016)
  30. Polymorphisms of β-defensin genes in Valle del Belice dairy sheep. Monteleone G, Calascibetta D, Scaturro M, Galluzzo P, Palmeri M, Riggio V, Portolano B. Mol Biol Rep 38 5405-5412 (2011)
  31. Preparation of isotopically labelled recombinant beta-defensin for NMR studies. Seo ES, Vargues T, Clarke DJ, Uhrín D, Campopiano DJ. Protein Expr Purif 65 179-184 (2009)
  32. Comparative simulation studies of native and single-site mutant human beta-defensin-1 peptides. Toubar RA, Zhmurov A, Barsegov V, Marx KA. J Biomol Struct Dyn 31 174-194 (2013)
  33. Chronic tonsillitis is not associated with beta defensin 1 gene polymorphisms in Turkish population. Arslan F, Babakurban ST, Erbek SS, Sahin FI, Terzi YK. Int J Pediatr Otorhinolaryngol 79 557-560 (2015)


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