Defensins (Homo sapiens)

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2717, 21, 293137, 184, 23, 2513, 20248, 95, 6, 28241, 1221151922, 302, 11, 14101631azurophil granule lumencytosolcytosolMicrobial cellviral envelopeGolgi lumensecretory granule lumenDEFB115(?-88) Lipid II DEFB103A(23-67) DEFB1(?-68) DEFA5(?-94) DEFB112(?-113) DEFB132(1-95) DEFA1(66-94) DEFA5(?-94)DEFB105A(1-78) Beta defensins4A,103:CCR2DEFB112(?-113) CCR6TLR1 omega-N-(ADP-ribosyl)-L-arginine-DEFA1(65-94)DEFB134(1-66) DEFB1(1-68) DEFB127(?-63) HNP1-3:gp120DEFB128(1-93) TLR1:TLR2DEFB108B(1-73) Surface protein gp120 DEFB103A(23-67) CD4DEFA1(66-94) DEFB106A(?-65) Defensins alpha1-3:CD4Beta-defensins DEFA5(20-94)DEFB132(?-95) Beta defensins1,4A,103DEFB132(?-95) DEFB123(?-67) DEFA1(65-94) DEFB113(?-82) DEFB106A(1-65) DEFB135(?-77) DEFA1(65-94) DEFA1(65-94) DEFA4(20-96) DEFA3(65-94) DEFB123(1-67) DEFB131(1-70) DEFB112(1-113) DEFB107A(?-70) TLR1 DEFB125(?-67) Anionic phospholipids Alpha-defensindimers:anionicphospholipidsDEFB104A(?-72) TLR2 DEFA1(1-94) DEFB118(1-62) DEFB108B(?-73) DEFB127(1-63) AnionicphospholipidsDEFB116(1-102) DEFA1(66-94) DEFA1(65-94) CD4 DEFB103A(23-67) Beta defensins 4A,103 DEFA6(1-100) DEFB114(?-69) Defensins that bindLipid IIAnionic phospholipids DEFB126(1-63) DEFB117(1-?) DEFB130(?-79) DEFB103A(23-67)DEFB117(?-?) Beta defensins 1,4A,103 Defensins alpha 1-4DEFA4(64-96) DEFB4A(?-64) Pro-defensins alpha1-4DEFA5(20-94) DEFB103A(1-67) Defensins alpha 1-4Alpha-defensindimersDEFA3(20-94) DEFA6(?-100) DEFB129(?-183) DEFA1(66-94) PRSS3 DEFB107A(1-70) DEFB135(?-77) DEFB116(?-102) DEFB4A(?-64) DEFB117(1-?) DEFB125(1-67) CCR2 DEFB135(1-77) DEFB136(?-78) DEFB105A(?-78) DEFB127(?-63) DEFB134(?-66) DEFB104A(1-72) Beta defensins4A,103DEFB115(?-88) DEFB104A(?-72) DEFA3(66-94) DEFB130(1-79) DEFB131(?-70) DEFA1(65-94) DEFA4(1-96) DEFB130(?-79) DEFB104A(?-72) DEFB106A(?-65) DEFB119(?-84) Beta-defensins:anionic phospholipidsDEFB132(?-95) DEFB105A(?-78) DEFA1(66-94) DEFB4A(?-64) DEFB124(1-71) DEFB4A(1-64) DEFB128(?-93) DEFB128(?-93) DEFB123(?-67) Anionic phospholipids DEFB112(?-113) DEFB125(?-67) DEFB103A(23-67) DEFA3(65-94) DEFB130(?-79) DEFB131(?-70) DEFB107A(?-70) DEFB114(?-69) DEFA1(66-94) DEFB105A(?-78) DEFA3(65-94) Alpha-defensinsDEFA3(66-94) DEFB1(?-68) DEFB127(?-63) DEFB118(?-62) TLR2 DEFA3(65-94) DEFB114(1-69) DEFB133(?-61) Pro-defensinsDEFB110(1-67) DEFB110(?-67) ART1Alpha-defensin dimers Defensins alpha 1-3 DEFA1(65-94) DEFA5(?-94) DEFB116(?-102) DEFB4A(?-64) DEFB135(?-77) DEFB133(?-61) Beta-defensinsDEFB133(?-61) DEFB118(?-62) gp120 homotrimerDEFB123(?-67) DEFB126(?-63) DEFB103A(23-67) DEFA1(65-94)DEFB110(?-67) DEFA4(64-96) DEFB117(?-?) DEFB1(?-68) Defensins alpha 1-3 DEFA6(20-100) Beta-defensinsDEFB136(?-78) Beta defensin103:TLR1:TLR2DEFB115(?-88) DEFA5(20-94)DEFB126(?-63) DEFA3(20-94) DEFB128(?-93) DEFA6(?-100) DEFA1(20-94) DEFB136(1-78) DEFB121(1-76) DEFA4(64-96) DEFA4(64-96) DEFB126(?-63) DEFA3(65-94) DEFB119(?-84) DEFA3(66-94) DEFB121(?-76) DEFB107A(?-70) CCR2DEFB134(?-66) DEFB125(?-67) DEFB113(?-82) Alpha-defensin dimers DEFB136(?-78) DEFB116(?-102) DEFB121(?-76) Alpha-defensin porecomplexDEFB115(1-88) Defensins that bindLipid II:Lipid IIDEFB103A(23-67) DEFB4A(?-64) Beta-defensins1,4A,103:CCR6DEFB134(?-66) DEFB119(?-84) DEFB118(?-62) DEFB108B(?-73) Pre-pro-defensinsDEFA4(20-96) DEFB124(?-71) DEFB129(1-183) DEFA1(65-94) DEFB131(?-70) DEFB106A(?-65) DEFB110(?-67) Lipid IIPRSS2 DEFA3(1-94) DEFB1(?-68) DEFB108B(?-73) DEFA3(66-94) DEFB114(?-69) DEFB129(?-183) CCR6 DEFB121(?-76) DEFA5(20-94)DEFA3(65-94) Defensins alpha 1-4DEFB113(?-82) DEFB124(?-71) DEFB103A(23-67) Defensins alpha 1-3DEFB124(?-71) DEFB119(1-84) DEFB133(1-61) DEFB129(?-183) DEFA5(1-94) Trypsin 2, 3Surface protein gp120 DEFB113(?-82) Defensins that bind Lipid II DEFA4(64-96) DEFA1(20-94) 26


Description

The defensins are a family of antimicrobial cationic peptide molecules which in mammals have a characteristic beta-sheet-rich fold and framework of six disulphide-linked cysteines (Selsted & Ouellette 2005, Ganz 2003). Human defensin peptides have two subfamilies, alpha- and beta-defensins, differing in the length of peptide chain between the six cysteines and the order of disulphide bond pairing between them. A third subfamily, the theta defensins, is derived from alpha-defensins prematurely truncated by a stop codon between the third and fourth cysteine residues. The translated products are shortened to nonapeptides, covalently dimerized by disulfide linkages, and cyclized via new peptide bonds between the first and ninth residues. Humans have one pseudogene but no translated representatives of the theta class.
In solution most alpha and beta defensins are monomers but can form dimers and higher order structures.

The primary cellular sources of defensins are neutrophils, epithelial cells and intestinal Paneth cells.Those expressed in neutrophils and the gut are predominantly constitutive, while those in epithelial tissues such as skin are often inducible by proinflammatory stimuli such as LPS or TNF-alpha.

Defensins are translated as precursor polypeptides that include a typical signal peptide or prepiece that is cleaved in the Golgi body, and a propiece, cleaved by differing mechanisms to produce the mature defensin. Mature defensin peptides can be further processed by removal of individual N-terminal residues (Yang et al. 2004). This may be a mechanism to broaden the activity profile of defensins (Ghosh et al. 2002).

Defensins have direct antimicrobial effects and kill a wide range of Gram-positive and negative bacteria, fungi and some viruses. The primary antimicrobial action of defensins is permeabilization of microbial target membranes but several additional mechanisms have been suggested (Brogden 2005, Wilmes et al. 2011). Defensins and related antimicrobial peptides such as cathelicidin bridge the innate and acquired immune responses. In addition to their antimicrobial properties, cathelicidin and several defensins show receptor-mediated chemotactic activity for immune cells such as monocytes, T cells or immature DCs, induce cytokine production by monocytes and epithelial cells, modulate angiogenesis and stimulate wound healing (Yang et al. 1999, 2000, 2004, Rehaume & Hancock 2008, Yeung et al. 2011).

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Bibliography

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  1. Wang W, Owen SM, Rudolph DL, Cole AM, Hong T, Waring AJ, Lal RB, Lehrer RI.; ''Activity of alpha- and theta-defensins against primary isolates of HIV-1.''; PubMed Europe PMC Scholia
  2. Szyk A, Wu Z, Tucker K, Yang D, Lu W, Lubkowski J.; ''Crystal structures of human alpha-defensins HNP4, HD5, and HD6.''; PubMed Europe PMC Scholia
  3. Valore EV, Ganz T.; ''Posttranslational processing of defensins in immature human myeloid cells.''; PubMed Europe PMC Scholia
  4. Sass V, Schneider T, Wilmes M, Körner C, Tossi A, Novikova N, Shamova O, Sahl HG.; ''Human beta-defensin 3 inhibits cell wall biosynthesis in Staphylococci.''; PubMed Europe PMC Scholia
  5. Niyonsaba F, Iwabuchi K, Matsuda H, Ogawa H, Nagaoka I.; ''Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway.''; PubMed Europe PMC Scholia
  6. Hill CP, Yee J, Selsted ME, Eisenberg D.; ''Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization.''; PubMed Europe PMC Scholia
  7. García JR, Jaumann F, Schulz S, Krause A, Rodríguez-Jiménez J, Forssmann U, Adermann K, Klüver E, Vogelmeier C, Becker D, Hedrich R, Forssmann WG, Bals R.; ''Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction.''; PubMed Europe PMC Scholia
  8. Garcia-Lopez G, Flores-Espinosa P, Zaga-Clavellina V.; ''Tissue-specific human beta-defensins (HBD)1, HBD2, and HBD3 secretion from human extra-placental membranes stimulated with Escherichia coli.''; PubMed Europe PMC Scholia
  9. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, Lee H, Lee JO.; ''Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.''; PubMed Europe PMC Scholia
  10. Harder J, Bartels J, Christophers E, Schroder JM.; ''Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.''; PubMed Europe PMC Scholia
  11. Ganz T.; ''Defensins: antimicrobial peptides of innate immunity.''; PubMed Europe PMC Scholia
  12. Lehrer RI.; ''Primate defensins.''; PubMed Europe PMC Scholia
  13. Yang D, Chen Q, Chertov O, Oppenheim JJ.; ''Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells.''; PubMed Europe PMC Scholia
  14. Zhang XL, Selsted ME, Pardi A.; ''NMR studies of defensin antimicrobial peptides. 1. Resonance assignment and secondary structure determination of rabbit NP-2 and human HNP-1.''; PubMed Europe PMC Scholia
  15. Wilde CG, Griffith JE, Marra MN, Snable JL, Scott RW.; ''Purification and characterization of human neutrophil peptide 4, a novel member of the defensin family.''; PubMed Europe PMC Scholia
  16. Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB, Ganz T.; ''Human beta-defensin-1: an antimicrobial peptide of urogenital tissues.''; PubMed Europe PMC Scholia
  17. Porter EM, Liu L, Oren A, Anton PA, Ganz T.; ''Localization of human intestinal defensin 5 in Paneth cell granules.''; PubMed Europe PMC Scholia
  18. Lehrer RI, Barton A, Daher KA, Harwig SS, Ganz T, Selsted ME.; ''Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity.''; PubMed Europe PMC Scholia
  19. de Leeuw E, Li C, Zeng P, Li C, Diepeveen-de Buin M, Lu WY, Breukink E, Lu W.; ''Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II.''; PubMed Europe PMC Scholia
  20. Hadjicharalambous C, Sheynis T, Jelinek R, Shanahan MT, Ouellette AJ, Gizeli E.; ''Mechanisms of alpha-defensin bactericidal action: comparative membrane disruption by Cryptdin-4 and its disulfide-null analogue.''; PubMed Europe PMC Scholia
  21. Röhrl J, Yang D, Oppenheim JJ, Hehlgans T.; ''Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2.''; PubMed Europe PMC Scholia
  22. Gullberg U, Bengtsson N, Bülow E, Garwicz D, Lindmark A, Olsson I.; ''Processing and targeting of granule proteins in human neutrophils.''; PubMed Europe PMC Scholia
  23. Paone G, Wada A, Stevens LA, Matin A, Hirayama T, Levine RL, Moss J.; ''ADP ribosylation of human neutrophil peptide-1 regulates its biological properties.''; PubMed Europe PMC Scholia
  24. Harwig SS, Park AS, Lehrer RI.; ''Characterization of defensin precursors in mature human neutrophils.''; PubMed Europe PMC Scholia
  25. Wimley WC, Selsted ME, White SH.; ''Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores.''; PubMed Europe PMC Scholia
  26. Ganz T, Liu L, Valore EV, Oren A.; ''Posttranslational processing and targeting of transgenic human defensin in murine granulocyte, macrophage, fibroblast, and pituitary adenoma cell lines.''; PubMed Europe PMC Scholia
  27. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schröder JM, Wang JM, Howard OM, Oppenheim JJ.; ''Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.''; PubMed Europe PMC Scholia
  28. Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI.; ''Defensins. Natural peptide antibiotics of human neutrophils.''; PubMed Europe PMC Scholia
  29. Lehrer RI, Ganz T.; ''Defensins: endogenous antibiotic peptides from human leukocytes.''; PubMed Europe PMC Scholia
  30. Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL.; ''Paneth cell trypsin is the processing enzyme for human defensin-5.''; PubMed Europe PMC Scholia
  31. Funderburg N, Lederman MM, Feng Z, Drage MG, Jadlowsky J, Harding CV, Weinberg A, Sieg SF.; ''Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114637view16:10, 25 January 2021ReactomeTeamReactome version 75
113085view11:14, 2 November 2020ReactomeTeamReactome version 74
112319view15:24, 9 October 2020ReactomeTeamReactome version 73
101218view11:11, 1 November 2018ReactomeTeamreactome version 66
100756view20:36, 31 October 2018ReactomeTeamreactome version 65
100300view19:13, 31 October 2018ReactomeTeamreactome version 64
99847view15:57, 31 October 2018ReactomeTeamreactome version 63
99404view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99094view12:39, 31 October 2018ReactomeTeamreactome version 62
93958view13:47, 16 August 2017ReactomeTeamreactome version 61
93554view11:27, 9 August 2017ReactomeTeamreactome version 61
87170view19:23, 18 July 2016MkutmonOntology Term : 'immune response pathway' added !
86656view09:23, 11 July 2016ReactomeTeamreactome version 56
83069view09:51, 18 November 2015ReactomeTeamVersion54
81386view12:54, 21 August 2015ReactomeTeamVersion53
76855view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76560view11:54, 16 July 2014ReactomeTeamFixed remaining interactions
75893view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75593view10:43, 10 June 2014ReactomeTeamReactome 48 Update
74948view13:47, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74864view14:17, 3 May 2014EgonwMarked a metabolite as a DataNode type="Metabolite"...
74592view08:38, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ART1ProteinP52961 (Uniprot-TrEMBL)
Alpha-defensin

dimers:anionic

phospholipids		ComplexR-HSA-1471345 (Reactome)
Alpha-defensin dimersComplexR-HSA-1471331 (Reactome)
Alpha-defensin dimers R-HSA-1471331 (Reactome)
Alpha-defensin pore complexComplexR-HSA-1471355 (Reactome)
Alpha-defensinsComplexR-HSA-1471333 (Reactome)
Anionic phospholipidsCHEBI:62643 (ChEBI)
Anionic phospholipids MetaboliteCHEBI:62643 (ChEBI)
Beta defensin 103:TLR1:TLR2ComplexR-HSA-1974673 (Reactome)
Beta defensins 1,4A,103ComplexR-HSA-1973976 (Reactome)
Beta defensins 4A,103:CCR2ComplexR-HSA-1973966 (Reactome)
Beta defensins 4A,103ComplexR-HSA-1973973 (Reactome)
Beta defensins 1,4A,103 R-HSA-1973976 (Reactome)
Beta defensins 4A,103 R-HSA-1973973 (Reactome)
Beta-defensins 1,4A,103:CCR6ComplexR-HSA-1471343 (Reactome)
Beta-defensins R-HSA-975681 (Reactome)
Beta-defensins:anionic phospholipidsComplexR-HSA-1471372 (Reactome)
Beta-defensinsComplexR-HSA-1471310 (Reactome)
Beta-defensinsComplexR-HSA-975681 (Reactome)
CCR2 ProteinP41597 (Uniprot-TrEMBL)
CCR2ProteinP41597 (Uniprot-TrEMBL)
CCR6 ProteinP51684 (Uniprot-TrEMBL)
CCR6ProteinP51684 (Uniprot-TrEMBL)
CD4 ProteinP01730 (Uniprot-TrEMBL)
CD4ProteinP01730 (Uniprot-TrEMBL)
DEFA1(1-94) ProteinP59665 (Uniprot-TrEMBL)
DEFA1(20-94) ProteinP59665 (Uniprot-TrEMBL)
DEFA1(65-94) ProteinP59665 (Uniprot-TrEMBL)
DEFA1(65-94)ProteinP59665 (Uniprot-TrEMBL)
DEFA1(66-94) ProteinP59665 (Uniprot-TrEMBL)
DEFA3(1-94) ProteinP59666 (Uniprot-TrEMBL)
DEFA3(20-94) ProteinP59666 (Uniprot-TrEMBL)
DEFA3(65-94) ProteinP59666 (Uniprot-TrEMBL)
DEFA3(66-94) ProteinP59666 (Uniprot-TrEMBL)
DEFA4(1-96) ProteinP12838 (Uniprot-TrEMBL)
DEFA4(20-96) ProteinP12838 (Uniprot-TrEMBL)
DEFA4(64-96) ProteinP12838 (Uniprot-TrEMBL)
DEFA5(1-94) ProteinQ01523 (Uniprot-TrEMBL)
DEFA5(20-94) ProteinQ01523 (Uniprot-TrEMBL)
DEFA5(20-94)ProteinQ01523 (Uniprot-TrEMBL)
DEFA5(?-94) ProteinQ01523 (Uniprot-TrEMBL)
DEFA5(?-94)ProteinQ01523 (Uniprot-TrEMBL)
DEFA6(1-100) ProteinQ01524 (Uniprot-TrEMBL)
DEFA6(20-100) ProteinQ01524 (Uniprot-TrEMBL)
DEFA6(?-100) ProteinQ01524 (Uniprot-TrEMBL)
DEFB1(1-68) ProteinP60022 (Uniprot-TrEMBL)
DEFB1(?-68) ProteinP60022 (Uniprot-TrEMBL)
DEFB103A(1-67) ProteinP81534 (Uniprot-TrEMBL)
DEFB103A(23-67) ProteinP81534 (Uniprot-TrEMBL)
DEFB103A(23-67)ProteinP81534 (Uniprot-TrEMBL)
DEFB104A(1-72) ProteinQ8WTQ1 (Uniprot-TrEMBL)
DEFB104A(?-72) ProteinQ8WTQ1 (Uniprot-TrEMBL)
DEFB105A(1-78) ProteinQ8NG35 (Uniprot-TrEMBL)
DEFB105A(?-78) ProteinQ8NG35 (Uniprot-TrEMBL)
DEFB106A(1-65) ProteinQ8N104 (Uniprot-TrEMBL)
DEFB106A(?-65) ProteinQ8N104 (Uniprot-TrEMBL)
DEFB107A(1-70) ProteinQ8IZN7 (Uniprot-TrEMBL)
DEFB107A(?-70) ProteinQ8IZN7 (Uniprot-TrEMBL)
DEFB108B(1-73) ProteinQ8NET1 (Uniprot-TrEMBL)
DEFB108B(?-73) ProteinQ8NET1 (Uniprot-TrEMBL)
DEFB110(1-67) ProteinQ30KQ9 (Uniprot-TrEMBL)
DEFB110(?-67) ProteinQ30KQ9 (Uniprot-TrEMBL)
DEFB112(1-113) ProteinQ30KQ8 (Uniprot-TrEMBL)
DEFB112(?-113) ProteinQ30KQ8 (Uniprot-TrEMBL)
DEFB113(?-82) ProteinQ30KQ7 (Uniprot-TrEMBL)
DEFB114(1-69) ProteinQ30KQ6 (Uniprot-TrEMBL)
DEFB114(?-69) ProteinQ30KQ6 (Uniprot-TrEMBL)
DEFB115(1-88) ProteinQ30KQ5 (Uniprot-TrEMBL)
DEFB115(?-88) ProteinQ30KQ5 (Uniprot-TrEMBL)
DEFB116(1-102) ProteinQ30KQ4 (Uniprot-TrEMBL)
DEFB116(?-102) ProteinQ30KQ4 (Uniprot-TrEMBL)
DEFB117(1-?) ProteinQ30KQ3 (Uniprot-TrEMBL)
DEFB117(?-?) ProteinQ30KQ3 (Uniprot-TrEMBL)
DEFB118(1-62) ProteinQ96PH6 (Uniprot-TrEMBL)
DEFB118(?-62) ProteinQ96PH6 (Uniprot-TrEMBL)
DEFB119(1-84) ProteinQ8N690 (Uniprot-TrEMBL)
DEFB119(?-84) ProteinQ8N690 (Uniprot-TrEMBL)
DEFB121(1-76) ProteinQ5J5C9 (Uniprot-TrEMBL)
DEFB121(?-76) ProteinQ5J5C9 (Uniprot-TrEMBL)
DEFB123(1-67) ProteinQ8N688 (Uniprot-TrEMBL)
DEFB123(?-67) ProteinQ8N688 (Uniprot-TrEMBL)
DEFB124(1-71) ProteinQ8NES8 (Uniprot-TrEMBL)
DEFB124(?-71) ProteinQ8NES8 (Uniprot-TrEMBL)
DEFB125(1-67) ProteinQ8N687 (Uniprot-TrEMBL)
DEFB125(?-67) ProteinQ8N687 (Uniprot-TrEMBL)
DEFB126(1-63) ProteinQ9BYW3 (Uniprot-TrEMBL)
DEFB126(?-63) ProteinQ9BYW3 (Uniprot-TrEMBL)
DEFB127(1-63) ProteinQ9H1M4 (Uniprot-TrEMBL)
DEFB127(?-63) ProteinQ9H1M4 (Uniprot-TrEMBL)
DEFB128(1-93) ProteinQ7Z7B8 (Uniprot-TrEMBL)
DEFB128(?-93) ProteinQ7Z7B8 (Uniprot-TrEMBL)
DEFB129(1-183) ProteinQ9H1M3 (Uniprot-TrEMBL)
DEFB129(?-183) ProteinQ9H1M3 (Uniprot-TrEMBL)
DEFB130(1-79) ProteinQ30KQ2 (Uniprot-TrEMBL)
DEFB130(?-79) ProteinQ30KQ2 (Uniprot-TrEMBL)
DEFB131(1-70) ProteinP59861 (Uniprot-TrEMBL)
DEFB131(?-70) ProteinP59861 (Uniprot-TrEMBL)
DEFB132(1-95) ProteinQ7Z7B7 (Uniprot-TrEMBL)
DEFB132(?-95) ProteinQ7Z7B7 (Uniprot-TrEMBL)
DEFB133(1-61) ProteinQ30KQ1 (Uniprot-TrEMBL)
DEFB133(?-61) ProteinQ30KQ1 (Uniprot-TrEMBL)
DEFB134(1-66) ProteinQ4QY38 (Uniprot-TrEMBL)
DEFB134(?-66) ProteinQ4QY38 (Uniprot-TrEMBL)
DEFB135(1-77) ProteinQ30KP9 (Uniprot-TrEMBL)
DEFB135(?-77) ProteinQ30KP9 (Uniprot-TrEMBL)
DEFB136(1-78) ProteinQ30KP8 (Uniprot-TrEMBL)
DEFB136(?-78) ProteinQ30KP8 (Uniprot-TrEMBL)
DEFB4A(1-64) ProteinO15263 (Uniprot-TrEMBL)
DEFB4A(?-64) ProteinO15263 (Uniprot-TrEMBL)
Defensins alpha 1-3:CD4ComplexR-HSA-1471352 (Reactome)
Defensins alpha 1-3 R-HSA-1471337 (Reactome)
Defensins alpha 1-3ComplexR-HSA-1471337 (Reactome)
Defensins alpha 1-4ComplexR-HSA-1470042 (Reactome)
Defensins alpha 1-4ComplexR-HSA-1470049 (Reactome)
Defensins alpha 1-4ComplexR-HSA-1471313 (Reactome)
Defensins that bind Lipid II:Lipid IIComplexR-HSA-1471328 (Reactome)
Defensins that bind Lipid IIComplexR-HSA-1973970 (Reactome)
Defensins that bind Lipid II R-HSA-1973970 (Reactome)
HNP1-3:gp120ComplexR-HSA-R-NUL-1471336 (Reactome)
Lipid II MetaboliteCHEBI:27692 (ChEBI)
Lipid IIMetaboliteCHEBI:27692 (ChEBI)
PRSS2 ProteinP07478 (Uniprot-TrEMBL)
PRSS3 ProteinP35030 (Uniprot-TrEMBL)
Pre-pro-defensinsComplexR-HSA-1467262 (Reactome)
Pro-defensins alpha 1-4ComplexR-HSA-1470043 (Reactome)
Pro-defensinsComplexR-HSA-1467213 (Reactome)
Surface protein gp120 ProteinP04578 (Uniprot-TrEMBL)
TLR1 ProteinQ15399 (Uniprot-TrEMBL)
TLR1:TLR2ComplexR-HSA-168946 (Reactome)
TLR2 ProteinO60603 (Uniprot-TrEMBL)
Trypsin 2, 3ComplexR-HSA-1460242 (Reactome)
gp120 homotrimerComplexR-HSA-R-HIV-173652 (Reactome)
omega-N-(ADP-ribosyl)-L-arginine-DEFA1(65-94)ProteinP59665 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ART1mim-catalysisR-HSA-1972385 (Reactome)
Alpha-defensin

dimers:anionic

phospholipids		ArrowR-HSA-1461971 (Reactome)
Alpha-defensin

dimers:anionic

phospholipids		R-HSA-1461982 (Reactome)
Alpha-defensin dimersArrowR-HSA-1462014 (Reactome)
Alpha-defensin dimersR-HSA-1461971 (Reactome)
Alpha-defensin pore complexArrowR-HSA-1461982 (Reactome)
Alpha-defensinsR-HSA-1462014 (Reactome)
Anionic phospholipidsR-HSA-1461971 (Reactome)
Anionic phospholipidsR-HSA-1467269 (Reactome)
Beta defensin 103:TLR1:TLR2ArrowR-HSA-1974676 (Reactome)
Beta defensins 1,4A,103R-HSA-1471338 (Reactome)
Beta defensins 4A,103:CCR2ArrowR-HSA-1973968 (Reactome)
Beta defensins 4A,103R-HSA-1973968 (Reactome)
Beta-defensins 1,4A,103:CCR6ArrowR-HSA-1471338 (Reactome)
Beta-defensins:anionic phospholipidsArrowR-HSA-1467269 (Reactome)
Beta-defensinsArrowR-HSA-1471322 (Reactome)
Beta-defensinsR-HSA-1467269 (Reactome)
Beta-defensinsR-HSA-1471322 (Reactome)
CCR2R-HSA-1973968 (Reactome)
CCR6R-HSA-1471338 (Reactome)
CD4R-HSA-1471314 (Reactome)
DEFA1(65-94)R-HSA-1972385 (Reactome)
DEFA5(20-94)ArrowR-HSA-1461995 (Reactome)
DEFA5(20-94)ArrowR-HSA-1462005 (Reactome)
DEFA5(20-94)R-HSA-1461993 (Reactome)
DEFA5(20-94)R-HSA-1461995 (Reactome)
DEFA5(20-94)R-HSA-1462005 (Reactome)
DEFA5(?-94)ArrowR-HSA-1461993 (Reactome)
DEFB103A(23-67)R-HSA-1974676 (Reactome)
Defensins alpha 1-3:CD4ArrowR-HSA-1471314 (Reactome)
Defensins alpha 1-3R-HSA-1471314 (Reactome)
Defensins alpha 1-3R-HSA-1471354 (Reactome)
Defensins alpha 1-4ArrowR-HSA-1462003 (Reactome)
Defensins alpha 1-4ArrowR-HSA-1462039 (Reactome)
Defensins alpha 1-4ArrowR-HSA-1462041 (Reactome)
Defensins alpha 1-4R-HSA-1462003 (Reactome)
Defensins alpha 1-4R-HSA-1462041 (Reactome)
Defensins that bind Lipid II:Lipid IIArrowR-HSA-1467209 (Reactome)
Defensins that bind Lipid IIR-HSA-1467209 (Reactome)
HNP1-3:gp120ArrowR-HSA-1471354 (Reactome)
Lipid IIR-HSA-1467209 (Reactome)
Pre-pro-defensinsR-HSA-1462023 (Reactome)
Pro-defensins alpha 1-4R-HSA-1462039 (Reactome)
Pro-defensinsArrowR-HSA-1462023 (Reactome)
R-HSA-1461971 (Reactome) The alpha-defensin dimers adsorb onto microbial membrane anionic phospholipids, represented here as a complex of alpha-defensin dimers and a representative set of phospholipid molecules 'membrane anionic phospholipids'. The polar topology of defensins, with their spatially separated charged and hydrophobic regions, allows them to insert into microbial cell membranes, which contains more negatively charged phospholipids than mammalian cell membranes (Lohner et al. 1997). Defensins permeabilize membrane vesicles (Lehrer et al. 1989) with a greater effect on vesicles rich in negatively charged phospholipids (Fuji et al. 1993, Wimley et al. 1994).
R-HSA-1461982 (Reactome) Once adsorbed/inserted into the membrane, alpha defensins are believed to aggregate into pore forming structures. Based on vesicle leakage and dextran permeability experiments, Wimley et al. (1994) proposed a multimeric pore model consisting of 6-8 defensin dimers which come together to form a large pore with inner diameter of 2-2.5nm. More recently using solid-state NMR and artificial lipid bilayers, Zhang et al. (2010) provide evidence of a dimer pore model in which the polar top of the dimer lines an aqueous pore while the hydrophobic bottom faces the lipid chains. Regardless of the exact conformation, the resulting pores then allow the efflux of essential microbial cell components.
R-HSA-1461993 (Reactome) Pro HD5 is stored and secreted from granules of Paneth cells in the small intestine (Porter et al. 1997, Cunliffe et al. 2001). The serine protease tryspin colocalizes to these granules as the inactive zymogen trypsinogen. Removal of the defensin propiece occurs extracellularly after release in to the crypt lumen, and is mediated by trypsin 2 (anionic trypsin) and/or trypsin-3 (mesotrypsin) which are converted to their active forms by enteroprotease like enzymes or by autoactivation (Ghosh et al. 2002, Ouelette 2011).
R-HSA-1461995 (Reactome) Pro-defensin alpha 5 is stored in the granules of Paneth cells in the small intestine (Porter et al. 1997). This pro-peptide has some antimicrobial activity but is not as effective as the mature peptide (Ghosh et al. 2002).
R-HSA-1462003 (Reactome) Alpha defensins HNP1-4, the neutrophil defensins, are stored in biologically active form in neutrophil primary (azurophil) granules, where they make up 5-10% of total cellular protein in these cells (Lehrere et al. 1993). The relative amounts of peptide for HNP-1 to -3 are 2:2:1 with HNP-4 being only a minor component.
R-HSA-1462005 (Reactome) Pro defensin alpha 5 is secreted from the storage granules of Paneth cells in the small intestine (Porter et al. 1997).
R-HSA-1462014 (Reactome) The crystal structure of human alpha-defensin HNP-3 revealed that it forms a dimer containing a six-stranded beta-sheet region (Hill et al. 1991). NMR studies indicate that HNP-1 can also form dimers or higher-order aggregates in solution and artificial lipid bilayers (Zhang et al. 1992, 2010a, 2010b). Models of alpha and beta defensins suggest that dimerization and/or higher order structures are characteristic, though not univeral or required for the biological effects of some beta-defensins (Suresh & Verma 2006, Pazgier et al. 2006).
R-HSA-1462023 (Reactome) Pre-pro-defensins are cleaved in the golgi by undefined proteases which remove the signal peptide (Yang et al. 2004, Pazgier et al. 2006). Subsequently, alpha-defensins are cleaved again to produce the biologically active mature peptide. Beta defensins have much shorter propieces and may be active once the signal peptide is removed. Further N-terminal processing of the mature defensin may yield multiple forms of the same peptide (Pazgier et al. 2006).
R-HSA-1462039 (Reactome) Synthesis of alpha defensins takes place in neutrophil precursor cells, the promyelocytes, in the bone marrow. Pro HNP1-4 are cleaved in the Golgi body, with HNP-2 being derived from cleavage of the N-terminal amino acid from HNP-1 or HNP-3. The defensin propiece is not only important for correct sub-cellular trafficking and sorting but also inhibits HNP activity (Valore et al. 1996, Wu et al. 2007). The resulting mature peptides are sorted to primary neutrophil (azurophil) granules for storage (Valore & Ganz 1992, Harwig et al. 1992, Cowland & Borregaard).
R-HSA-1462041 (Reactome) Human neutrophils contain thousands of cytoplasmic granules. These membrane-bound organelles act as storage compartments destined for secretion or in the case of azurophil granules, destined for fusion with phagosomes. A small amount of defensin, but perhaps not enough for antimicrobial activity, may be released extracellularly by neutrophils (Ganz 1987).
R-HSA-1467209 (Reactome) In S. aureus, rather than cause gross membrane changes, HNP-1 (de Leeuw et al. 2010) and hBD3 (Sass et al. 2011) appear to interfere with cell wall biosynthetic pathways by binding to Lipid II (undecaprenylpyrophosphate-MurNAc[pentapeptide]-GlcNAc), an essential precursor of bacterial cell walls and the target of several antibiotics (Breukink & de Krujiff 2007). The transformation of monomeric lipid II into a polymeric peptidoglycan by the bifunctional S. aureus enzyme Penicillin-binding protein 2 (PBP2) is inhibited by hBD3 (Sass et al. 2011) resulting in local lesions of the cell wall layer through which membranes and cytoplasmic contents ultimately protrude.
R-HSA-1467269 (Reactome) Binding and disruption of microbial membranes is widely believed to be the primary mechanism of action for beta-defensins. There is no direct evidence of this, but a growing number of studies support this model (Pazgier et al. 2006). Beta-defensins have antimicrobial properties that correlate with membrane permeabilization effects (Antcheva et al. 2004, Sahl et al. 2005, Yenugu et al. 2004). The sensitivity of microbes to beta-defensins correlates with the lipid composition of the membrane; more negatively-charged lipids correlate with larger beta-defensin 103-induced changes in membrane capacitance (Bohling et al. 2006). Beta-defensin-103 was observed to give rise to ionic currents in Xenopus membranes (Garcia et al. 2001) and cell wall perforation was observed in S. aureus when treated with HBD-3 (Harder et al. 2001). Two models explain how membrane disruption takes place. The 'pore model' postulates that beta-defenisns form transmembrane pores in a similar manner to alpha-defensins, while the 'carpet model' suggests that beta-defensins act as detergents, causing a less organised disruption. Beta-defensins have a structure that is topologically distinct from that of alpha-defensins, suggesting a different mode of dimerization and an electrostatic charge-based mechanism of membrane permeabilization rather than a mechanism based on formation of bilayer-spanning pores (Hoover et al. 2000).
R-HSA-1471314 (Reactome) Alpha-defensins, theta-defensins and their synthetic analogues the retrocyclins have been shown in numerous studies to have anti-HIV-1 activity (Chang & Klotman 2004). This appears to be mediated via multiple mechanisms including direct viral inactivation and down regulation of host-cell target co-receptors important for viral entry (Furci et al. 2007, Seidel et al. 2010). Further, HNPs 1 3, act as lectins and bind with relatively high affinity to gp120 (KD range, 15.8-52.8 nM) on the HIV-1 envelope and CD4 (KD range, 8.0-34.9 nM) on host target cells, both important molecules for viral entry (Wang et al. 2004). Artificial theta defensins, the retrocyclins, predicted from the human pseudogenes bind with even higher affinity whereas HNP-4 binding is much weaker (Wu et al. 2005). Alpha defensins have been demonstrated to inhibit the binding of gp120 to CD4 thus blocking HIV-1 fusion with its target cells (Furci et al. 2007).
R-HSA-1471322 (Reactome) Beta defensin precursors are more simple in structure than those of alpha defensins, having a signal sequence, a short or absent propiece and the mature defensin sequence at the C-terminus. The signal sequence is cleaved off by a signal peptidase in the endoplasmic reticulum (Ganz 2003). Mature beta defensins 1, 2, 3, and 4 are secreted primarily by epithelial cells but are also produced by some immune cells such as monocytes, macrophages and dendritic cells (Duits et al. 2000, Ryan et al. 2003).
R-HSA-1471338 (Reactome) The chemotactic activity of beta-defensins 1, 4A and 103 (hBD1-3) for immune and inflammatory cells such as memory T cells and immature dendritic cells is mediated through binding to the chemokine receptor CCR6.
R-HSA-1471354 (Reactome) Alpha-defensins, theta-defensins and their synthetic analogues the retrocyclins have been shown in numerous studies to have anti-HIV-1 activity (Chang & Klotman 2004). This appears to be mediated via multiple mechanisms including direct viral inactivation and down regulation of host-cell target co-receptors important for viral entry (Furci et al. 2007, Seidel et al. 2010). HNP1-3 act as lectins, binding with relatively high affinity to gp120 (KD range, 15.8-52.8 nM) on the HIV-1 envelope and CD4 (KD range, 8.0-34.9 nM) on host target cells, both important molecules for viral entry (Wang et al. 2004). Retrocyclins, artificial theta defensins predicted from human defensin pseudogenes, bind with even higher affinity whereas HNP-4 binding is much weaker (Wu et al. 2005). Alpha defensins have been demonstrated to inhibit the binding of gp120 to CD4 thus blocking HIV-1 fusion with its target cells (Furci et al. 2007).
R-HSA-1972385 (Reactome) HNP-1 is recognized as a substrate by arginine-specific ADP-ribosyltransferase-1 which ribosylates Arg-14 of the peptide. The modified defensin has reduced antimicrobial and cytotoxic activities but its chemotactic properties remain unchanged whilst its ability to induced the chemokine IL-8 is enhanced.
R-HSA-1973968 (Reactome) human beta-defensin (hBD)4A and 103 interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils.
R-HSA-1974676 (Reactome) Beta defensin 103 (hBD-3) can induce expression of the costimulatory molecules CD80, CD86 and CD40 on monocytes and myeloid dendritic cells in a Toll-like receptor (TLR)-dependent manner. Activation by hBD-3 is mediated by an interaction that requires TLRs 1 and 2 (Funderburg et al. 2007, 2011).
TLR1:TLR2R-HSA-1974676 (Reactome)
Trypsin 2, 3mim-catalysisR-HSA-1461993 (Reactome)
gp120 homotrimerR-HSA-1471354 (Reactome)
omega-N-(ADP-ribosyl)-L-arginine-DEFA1(65-94)ArrowR-HSA-1972385 (Reactome)
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