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Trp-26 imparts functional versatility to human alpha-defensin HNP1.

Wei G, Pazgier M, de Leeuw E, Rajabi M, Li J, Zou G, Jung G, Yuan W, Lu WY, Lehrer RI, Lu W
J Biol Chem 285 16275-85 (2010)
Related entries: 3h6c, 3lo1, 3lo2, 3lo4, 3lo9, 3loe, 3lvx

Cited: 38 times
EuropePMC logo PMID: 20220136

Abstract

We performed a comprehensive alanine scan of human alpha-defensin HNP1 and tested the ability of the resulting analogs to kill Staphylococcus aureus, inhibit anthrax lethal factor, and bind human immunodeficiency virus-1 gp120. By far, the most deleterious mutation for all of these functions was W26A. The activities lost by W26A-HNP1 were restored progressively by replacing W26 with non-coded, straight-chain aliphatic amino acids of increasing chain length. The hydrophobicity of residue 26 also correlated with the ability of the analogs to bind immobilized wild type HNP1 and to undergo further self-association. Thus, the hydrophobicity of residue 26 is not only a key determinant of the direct interactions of HNP1 with target molecules, but it also governs the ability of this peptide to form dimers and more complex quaternary structures at micromolar concentrations. Although all defensin peptides are cationic, their amphipathicity is at least as important as their positive charge in enabling them to participate in innate host defense.

Articles - 3lo6 mentioned but not cited (1)

  1. Trp-26 imparts functional versatility to human alpha-defensin HNP1. Wei G, Pazgier M, de Leeuw E, Rajabi M, Li J, Zou G, Jung G, Yuan W, Lu WY, Lehrer RI, Lu W. J Biol Chem 285 16275-16285 (2010)


Reviews citing this publication (9)

  1. α-Defensins in human innate immunity. Lehrer RI, Lu W. Immunol Rev 245 84-112 (2012)
  2. Antiviral mechanisms of human defensins. Wilson SS, Wiens ME, Smith JG. J Mol Biol 425 4965-4980 (2013)
  3. Perspectives for clinical use of engineered human host defense antimicrobial peptides. Pachón-Ibáñez ME, Smani Y, Pachón J, Sánchez-Céspedes J. FEMS Microbiol Rev 41 323-342 (2017)
  4. Defensins in innate immunity. Zhao L, Lu W. Curr Opin Hematol 21 37-42 (2014)
  5. Antiviral Activities of Human Host Defense Peptides. Brice DC, Diamond G. Curr Med Chem 27 1420-1443 (2020)
  6. Amyloid formation: functional friend or fearful foe? Bergman P, Roan NR, Römling U, Bevins CL, Münch J. J Intern Med 280 139-152 (2016)
  7. Targeting and inactivation of bacterial toxins by human defensins. Kudryashova E, Seveau SM, Kudryashov DS. Biol Chem 398 1069-1085 (2017)
  8. Synthesis and bioactivity of antitubercular peptides and peptidomimetics: an update. De Leon Rodriguez LM, Kaur H, Brimble MA. Org Biomol Chem 14 1177-1187 (2016)
  9. General lack of structural characterization of chemically synthesized long peptides. Boutin JA, Tartar AL, van Dorsselaer A, Vaudry H. Protein Sci 28 857-867 (2019)

Articles citing this publication (28)

  1. Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Chu H, Pazgier M, Jung G, Nuccio SP, Castillo PA, de Jong MF, Winter MG, Winter SE, Wehkamp J, Shen B, Salzman NH, Underwood MA, Tsolis RM, Young GM, Lu W, Lehrer RI, Bäumler AJ, Bevins CL. Science 337 477-481 (2012)
  2. Phosphoinositide-mediated oligomerization of a defensin induces cell lysis. Poon IKh, Baxter AA, Lay FT, Mills GD, Adda CG, Payne JA, Phan TK, Ryan GF, White JA, Veneer PK, van der Weerden NL, Anderson MA, Kvansakul M, Hulett MD. Elife 3 e01808 (2014)
  3. Multifaceted mechanisms of HIV-1 entry inhibition by human α-defensin. Demirkhanyan LH, Marin M, Padilla-Parra S, Zhan C, Miyauchi K, Jean-Baptiste M, Novitskiy G, Lu W, Melikyan GB. J Biol Chem 287 28821-28838 (2012)
  4. Functional determinants of human enteric α-defensin HD5: crucial role for hydrophobicity at dimer interface. Rajabi M, Ericksen B, Wu X, de Leeuw E, Zhao L, Pazgier M, Lu W. J Biol Chem 287 21615-21627 (2012)
  5. Critical determinants of human α-defensin 5 activity against non-enveloped viruses. Gounder AP, Wiens ME, Wilson SS, Lu W, Smith JG. J Biol Chem 287 24554-24562 (2012)
  6. Human defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment. Rapista A, Ding J, Benito B, Lo YT, Neiditch MB, Lu W, Chang TL. Retrovirology 8 45 (2011)
  7. Human defensins facilitate local unfolding of thermodynamically unstable regions of bacterial protein toxins. Kudryashova E, Quintyn R, Seveau S, Lu W, Wysocki VH, Kudryashov DS. Immunity 41 709-721 (2014)
  8. 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)
  9. Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation. Brook M, Tomlinson GH, Miles K, Smith RW, Rossi AG, Hiemstra PS, van 't Wout EF, Dean JL, Gray NK, Lu W, Gray M. Proc Natl Acad Sci U S A 113 4350-4355 (2016)
  10. Sometimes it takes two to tango: contributions of dimerization to functions of human α-defensin HNP1 peptide. Pazgier M, Wei G, Ericksen B, Jung G, Wu Z, de Leeuw E, Yuan W, Szmacinski H, Lu WY, Lubkowski J, Lehrer RI, Lu W. J Biol Chem 287 8944-8953 (2012)
  11. Oligoarginine-modified biodegradable nanoparticles improve the intestinal absorption of insulin. Liu X, Liu C, Zhang W, Xie C, Wei G, Lu W. Int J Pharm 448 159-167 (2013)
  12. Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. Varney KM, Bonvin AM, Pazgier M, Malin J, Yu W, Ateh E, Oashi T, Lu W, Huang J, Diepeveen-de Buin M, Bryant J, Breukink E, Mackerell AD, de Leeuw EP. PLoS Pathog 9 e1003732 (2013)
  13. 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)
  14. Alarmin HNP-1 promotes pyroptosis and IL-1β release through different roles of NLRP3 inflammasome via P2X7 in LPS-primed macrophages. Chen Q, Jin Y, Zhang K, Li H, Chen W, Meng G, Fang X. Innate Immun 20 290-300 (2014)
  15. NMR solution structure and condition-dependent oligomerization of the antimicrobial peptide human defensin 5. Wommack AJ, Robson SA, Wanniarachchi YA, Wan A, Turner CJ, Wagner G, Nolan EM. Biochemistry 51 9624-9637 (2012)
  16. Human Enteric α-Defensin 5 Promotes Shigella Infection by Enhancing Bacterial Adhesion and Invasion. Xu D, Liao C, Zhang B, Tolbert WD, He W, Dai Z, Zhang W, Yuan W, Pazgier M, Liu J, Yu J, Sansonetti PJ, Bevins CL, Shao Y, Lu W. Immunity 48 1233-1244.e6 (2018)
  17. Single, double and quadruple alanine substitutions at oligomeric interfaces identify hydrophobicity as the key determinant of human neutrophil alpha defensin HNP1 function. Zhao L, Tolbert WD, Ericksen B, Zhan C, Wu X, Yuan W, Li X, Pazgier M, Lu W. PLoS One 8 e78937 (2013)
  18. Invariant gly residue is important for α-defensin folding, dimerization, and function: a case study of the human neutrophil α-defensin HNP1. Zhao L, Ericksen B, Wu X, Zhan C, Yuan W, Li X, Pazgier M, Lu W. J Biol Chem 287 18900-18912 (2012)
  19. Quantification of polysaccharides fixed to Gram stained slides using lactophenol cotton blue and digital image processing. Ericksen B. F1000Res 4 1 (2015)
  20. Hydrophobic determinants of α-defensin bactericidal activity. Tai KP, Le VV, Selsted ME, Ouellette AJ. Infect Immun 82 2195-2202 (2014)
  21. Proteinase 3 carries small unusual carbohydrates and associates with αlpha-defensins. Zoega M, Ravnsborg T, Højrup P, Houen G, Schou C. J Proteomics 75 1472-1485 (2012)
  22. Human defensin-inspired discovery of peptidomimetic antibiotics. Luo G, Zhang J, Wang H, Sun Y, Cheng B, Xu Z, Zhang Y, Li H, Lu W, Nemeth E, Ganz T, Fang X. Proc Natl Acad Sci U S A 119 e2117283119 (2022)
  23. Thermodynamic instability of viral proteins is a pathogen-associated molecular pattern targeted by human defensins. Kudryashova E, Koneru PC, Kvaratskhelia M, Strömstedt AA, Lu W, Kudryashov DS. Sci Rep 6 32499 (2016)
  24. Insights into Protein Structure and Dynamics by Ultraviolet and Visible Resonance Raman Spectroscopy. López-Peña I, Leigh BS, Schlamadinger DE, Kim JE. Biochemistry 54 4770-4783 (2015)
  25. Lipid composition is a determinant for human defensin HNP1 selectivity. Gonçalves S, Abade J, Teixeira A, Santos NC. Biopolymers 98 313-321 (2012)
  26. Nonenzymatic conversion of ADP-ribosylated arginines to ornithine alters the biological activities of human neutrophil peptide-1. Stevens LA, Barbieri JT, Piszczek G, Otuonye AN, Levine RL, Zheng G, Moss J. J Immunol 193 6144-6151 (2014)
  27. Mouse α-Defensins: Structural and Functional Analysis of the 17 Cryptdin Isoforms Identified from a Single Jejunal Crypt. Wang Q, Yang Y, Luo G, Zhou Y, Tolbert WD, Pazgier M, Liao C, Lu W. Infect Immun 91 e0036122 (2023)
  28. Apparent instability of crystallographic refinement in the presence of disordered model fragments and upon insufficiently restrained model geometry. Pozharski E. Acta Crystallogr D Biol Crystallogr 67 966-972 (2011)


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