DFB4A_HUMAN
ID DFB4A_HUMAN Reviewed; 64 AA.
AC O15263; Q52LC0;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Defensin beta 4A {ECO:0000312|HGNC:HGNC:2767};
DE AltName: Full=Beta-defensin 2 {ECO:0000303|PubMed:9202117};
DE Short=BD-2 {ECO:0000303|PubMed:9202117};
DE Short=hBD-2 {ECO:0000303|PubMed:9202117};
DE AltName: Full=Defensin, beta 2;
DE AltName: Full=Skin-antimicrobial peptide 1;
DE Short=SAP1;
DE Flags: Precursor;
GN Name=DEFB4A; Synonyms=DEFB102, DEFB2, DEFB4;
GN and
GN Name=DEFB4B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND INDUCTION BY
RP TNF AND MICROORGANISMS.
RC TISSUE=Skin;
RX PubMed=9202117; DOI=10.1038/43088;
RA Harder J., Bartels J.H., Christophers E., Schroeder J.-M.;
RT "A peptide antibiotic from human skin.";
RL Nature 387:861-861(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY, AND INDUCTION BY
RP INFLAMMATION.
RC TISSUE=Placenta;
RX PubMed=9831658; DOI=10.1016/s0378-1119(98)00480-6;
RA Liu L., Wang L., Jia H.P., Zhao C., Heng H.H.Q., Schutte B.C.,
RA McCray P.B. Jr., Ganz T.;
RT "Structure and mapping of the human beta-defensin HBD-2 gene and its
RT expression at sites of inflammation.";
RL Gene 222:237-244(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10603376; DOI=10.1128/iai.68.1.113-119.2000;
RA Diamond G., Kaiser V., Rhodes J., Russell J.P., Bevins C.L.;
RT "Transcriptional regulation of beta-defensin gene expression in tracheal
RT epithelial cells.";
RL Infect. Immun. 68:113-119(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND INDUCTION BY P.AERUGINOSA; LPS; TNF AND IL1B.
RX PubMed=10837369; DOI=10.1165/ajrcmb.22.6.4023;
RA Harder J., Meyer-Hoffert U., Teran L.M., Schwichtenberg L., Bartels J.,
RA Maune S., Schroeder J.-M.;
RT "Mucoid Pseudomonas aeruginosa, TNF-alpha, and IL-1beta, but not IL-6,
RT induce human beta-defensin-2 in respiratory epithelia.";
RL Am. J. Respir. Cell Mol. Biol. 22:714-721(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION.
RX PubMed=10521347; DOI=10.1126/science.286.5439.525;
RA Yang D., Chertov O., Bykovskaia S.N., Chen Q., Buffo M.J., Shogan J.,
RA Anderson M., Schroeder J.M., Wang J.M., Howard O.M., Oppenheim J.J.;
RT "Beta-defensins: linking innate and adaptive immunity through dendritic and
RT T cell CCR6.";
RL Science 286:525-528(1999).
RN [7]
RP SYNTHESIS OF 24-64.
RX PubMed=12010514; DOI=10.1034/j.1399-3011.2002.00980.x;
RA Kluever E., Schulz A., Forssmann W.-G., Adermann K.;
RT "Chemical synthesis of beta-defensins and LEAP-1/hepcidin.";
RL J. Pept. Res. 59:241-248(2002).
RN [8]
RP FUNCTION, AND BINDING TO CCR6.
RX PubMed=20068036; DOI=10.1074/jbc.m109.091090;
RA Roehrl J., Yang D., Oppenheim J.J., Hehlgans T.;
RT "Specific binding and chemotactic activity of mBD4 and its functional
RT orthologue hBD2 to CCR6-expressing cells.";
RL J. Biol. Chem. 285:7028-7034(2010).
RN [9] {ECO:0007744|PDB:1FD3, ECO:0007744|PDB:1FD4}
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 24-64, SUBUNIT, AND DISULFIDE
RP BONDS.
RX PubMed=10906336; DOI=10.1074/jbc.m006098200;
RA Hoover D.M., Rajashankar K.R., Blumenthal R., Puri A., Oppenheim J.J.,
RA Chertov O., Lubkowski J.;
RT "The structure of human beta-defensin-2 shows evidence of higher order
RT oligomerization.";
RL J. Biol. Chem. 275:32911-32918(2000).
RN [10] {ECO:0007744|PDB:1FQQ}
RP STRUCTURE BY NMR OF 24-64, SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=11300761; DOI=10.1021/bi002519d;
RA Sawai M.V., Jia H.P., Liu L., Aseyev V., Wiencek J.M., McCray P.B.,
RA Ganz T., Kearney W.R., Tack B.F.;
RT "The NMR structure of human beta-defensin-2 reveals a novel alpha-helical
RT segment.";
RL Biochemistry 40:3810-3816(2001).
RN [11] {ECO:0007744|PDB:1E4Q}
RP STRUCTURE BY NMR OF 28-64, AND DISULFIDE BONDS.
RX PubMed=11714914; DOI=10.1110/ps.24401;
RA Bauer F., Schweimer K., Kluever E., Conejo-Garcia J.-R., Forssmann W.-G.,
RA Roesch P., Adermann K., Sticht H.;
RT "Structure determination of human and murine beta-defensins reveals
RT structural conservation in the absence of significant sequence
RT similarity.";
RL Protein Sci. 10:2470-2479(2001).
RN [12] {ECO:0007744|PDB:6CS9}
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 24-64 IN COMPLEX WITH PIP2,
RP FUNCTION, DISULFIDE BONDS, AND MUTAGENESIS OF LYS-33; ARG-45; ARG-46;
RP TYR-47; LYS-48 AND LYS-59.
RX PubMed=30050988; DOI=10.1126/sciadv.aat0979;
RA Jaervaa M., Phan T.K., Lay F.T., Caria S., Kvansakul M., Hulett M.D.;
RT "Human beta-defensin 2 kills Candida albicans through phosphatidylinositol
RT 4,5-bisphosphate-mediated membrane permeabilization.";
RL Sci. Adv. 4:eaat0979-eaat0979(2018).
CC -!- FUNCTION: Exhibits antimicrobial activity against Gram-negative
CC bacteria and Gram-positive bacteria, with highest activity against
CC Gram-negative bacteria (PubMed:9202117, PubMed:10837369). Antimicrobial
CC activity against P.aruginosa seems to be salt-sensitive and is reduced
CC with high salt concentrations greater than 25 mM (PubMed:10837369).
CC Also exhibits antimicrobial activity against the yeast C.albicans
CC (PubMed:9202117, PubMed:10837369, PubMed:30050988). Permeabilizes
CC C.albicans cell membranes via targeting plasma membrane lipid
CC phosphatidylinositol 4,5-bisphosphate (PIP2), thereby leading to cell
CC fragmentation and cell death (PubMed:30050988). Acts as a ligand for C-
CC C chemokine receptor CCR6 (PubMed:10521347, PubMed:20068036). Binds to
CC CCR6 and induces chemotactic activity of CCR6-expressing cells, such as
CC immature dendritic cells and memory T cells (PubMed:10521347,
CC PubMed:20068036). {ECO:0000269|PubMed:10521347,
CC ECO:0000269|PubMed:10837369, ECO:0000269|PubMed:20068036,
CC ECO:0000269|PubMed:30050988, ECO:0000269|PubMed:9202117}.
CC -!- SUBUNIT: Monomer (PubMed:11300761). Homodimer (PubMed:10906336).
CC {ECO:0000269|PubMed:10906336, ECO:0000269|PubMed:11300761}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10837369}.
CC -!- TISSUE SPECIFICITY: Expressed in lung epithelial cells (at protein
CC level) (PubMed:10837369). Expressed in foreskin, lung and trachea
CC (PubMed:9202117). Lower expression in kidney, uterus and salivary gland
CC tissue (PubMed:9202117). Expressed in epithelial cells of the
CC respiratory tract, with higher expression in distal parenchyma of the
CC lung, trachea, and tonsils, and lower expression in pharynx and
CC adenoid, and low expression in tongue and larynx (PubMed:9831658,
CC PubMed:10837369). {ECO:0000269|PubMed:10837369,
CC ECO:0000269|PubMed:9202117, ECO:0000269|PubMed:9831658}.
CC -!- INDUCTION: Up-regulated by TNF, IL1B, Gram-negative and Gram-positive
CC bacteria, C.albicans and bacterial lipopolysaccharides (LPS)
CC (PubMed:9202117, PubMed:10837369). Up-regulated by inflammation in skin
CC keratinocytes in epidermal tissue (PubMed:9831658).
CC {ECO:0000269|PubMed:10837369, ECO:0000269|PubMed:9202117,
CC ECO:0000269|PubMed:9831658}.
CC -!- SIMILARITY: Belongs to the beta-defensin family. LAP/TAP subfamily.
CC {ECO:0000305}.
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DR EMBL; Z71389; CAA95992.1; -; mRNA.
DR EMBL; AF040153; AAC33549.1; -; Genomic_DNA.
DR EMBL; AF071216; AAC69554.1; -; Genomic_DNA.
DR EMBL; AJ000152; CAB65126.1; -; Genomic_DNA.
DR EMBL; BC069285; AAH69285.1; -; mRNA.
DR EMBL; BC093983; AAH93983.1; -; mRNA.
DR EMBL; BC093985; AAH93985.1; -; mRNA.
DR CCDS; CCDS5971.1; -.
DR RefSeq; NP_001192195.1; NM_001205266.1.
DR RefSeq; NP_004933.1; NM_004942.3.
DR PDB; 1E4Q; NMR; -; A=28-64.
DR PDB; 1FD3; X-ray; 1.35 A; A/B/C/D=24-64.
DR PDB; 1FD4; X-ray; 1.70 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=24-64.
DR PDB; 1FQQ; NMR; -; A=24-64.
DR PDB; 6CS9; X-ray; 1.85 A; A/B=24-64.
DR PDBsum; 1E4Q; -.
DR PDBsum; 1FD3; -.
DR PDBsum; 1FD4; -.
DR PDBsum; 1FQQ; -.
DR PDBsum; 6CS9; -.
DR AlphaFoldDB; O15263; -.
DR SMR; O15263; -.
DR BioGRID; 108037; 3.
DR IntAct; O15263; 1.
DR STRING; 9606.ENSP00000303532; -.
DR TCDB; 1.C.85.1.2; the pore-forming Beta-defensin (Beta-defensin) family.
DR BioMuta; DEFB4A; -.
DR MassIVE; O15263; -.
DR PaxDb; O15263; -.
DR PeptideAtlas; O15263; -.
DR PRIDE; O15263; -.
DR ProteomicsDB; 48551; -.
DR Antibodypedia; 22053; 217 antibodies from 18 providers.
DR Antibodypedia; 4918; 175 antibodies from 20 providers.
DR DNASU; 1673; -.
DR Ensembl; ENST00000302247.3; ENSP00000303532.2; ENSG00000171711.3.
DR Ensembl; ENST00000318157.3; ENSP00000424598.1; ENSG00000177257.3.
DR Ensembl; ENST00000617136.2; ENSP00000479138.1; ENSG00000275444.2.
DR Ensembl; ENST00000642856.2; ENSP00000496499.1; ENSG00000285181.2.
DR Ensembl; ENST00000644124.2; ENSP00000493760.1; ENSG00000285433.2.
DR GeneID; 100289462; -.
DR GeneID; 1673; -.
DR KEGG; hsa:100289462; -.
DR KEGG; hsa:1673; -.
DR MANE-Select; ENST00000302247.3; ENSP00000303532.2; NM_004942.4; NP_004933.1.
DR MANE-Select; ENST00000318157.3; ENSP00000424598.1; NM_001205266.2; NP_001192195.1.
DR UCSC; uc003wsd.4; human.
DR CTD; 100289462; -.
DR CTD; 1673; -.
DR DisGeNET; 100289462; -.
DR DisGeNET; 1673; -.
DR GeneCards; DEFB4A; -.
DR GeneCards; DEFB4B; -.
DR HGNC; HGNC:2767; DEFB4A.
DR HGNC; HGNC:30193; DEFB4B.
DR HPA; ENSG00000171711; Tissue enriched (esophagus).
DR HPA; ENSG00000177257; Group enriched (esophagus, lymphoid tissue).
DR MIM; 602215; gene.
DR neXtProt; NX_O15263; -.
DR OpenTargets; ENSG00000171711; -.
DR OpenTargets; ENSG00000177257; -.
DR PharmGKB; PA27249; -.
DR VEuPathDB; HostDB:ENSG00000171711; -.
DR VEuPathDB; HostDB:ENSG00000177257; -.
DR eggNOG; ENOG502SYUI; Eukaryota.
DR GeneTree; ENSGT00940000160995; -.
DR HOGENOM; CLU_189296_4_1_1; -.
DR InParanoid; O15263; -.
DR OMA; IRSGAIC; -.
DR OrthoDB; 1584343at2759; -.
DR PhylomeDB; O15263; -.
DR PathwayCommons; O15263; -.
DR Reactome; R-HSA-1461957; Beta defensins.
DR Reactome; R-HSA-1461973; Defensins.
DR SignaLink; O15263; -.
DR BioGRID-ORCS; 100289462; 12 hits in 982 CRISPR screens.
DR BioGRID-ORCS; 1673; 61 hits in 967 CRISPR screens.
DR EvolutionaryTrace; O15263; -.
DR GeneWiki; Beta-defensin_2; -.
DR Pharos; O15263; Tbio.
DR PRO; PR:O15263; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; O15263; protein.
DR Bgee; ENSG00000171711; Expressed in mucosa of stomach and 56 other tissues.
DR Genevisible; O15263; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0031731; F:CCR6 chemokine receptor binding; IDA:UniProtKB.
DR GO; GO:0042056; F:chemoattractant activity; IBA:GO_Central.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0061760; P:antifungal innate immune response; IDA:UniProtKB.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IDA:UniProtKB.
DR GO; GO:0060326; P:cell chemotaxis; IBA:GO_Central.
DR GO; GO:0006935; P:chemotaxis; IDA:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IMP:MGI.
DR GO; GO:0050832; P:defense response to fungus; IDA:UniProtKB.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IDA:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:ProtInc.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0031640; P:killing of cells of another organism; IDA:UniProtKB.
DR GO; GO:0051673; P:membrane disruption in another organism; IDA:UniProtKB.
DR InterPro; IPR001855; Defensin_beta-typ.
DR InterPro; IPR006080; Defensin_beta/alpha.
DR Pfam; PF00711; Defensin_beta; 1.
DR SMART; SM00048; DEFSN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antibiotic; Antimicrobial; Defensin; Disulfide bond;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT PEPTIDE 24..64
FT /note="Defensin beta 4A"
FT /id="PRO_0000006968"
FT REGION 33..48
FT /note="Phosphatidylinositol 4,5-bisphosphate (PIP2)
FT binding"
FT /evidence="ECO:0000269|PubMed:30050988"
FT DISULFID 31..60
FT /evidence="ECO:0000269|PubMed:10906336,
FT ECO:0000269|PubMed:11300761, ECO:0000269|PubMed:11714914,
FT ECO:0000269|PubMed:30050988, ECO:0007744|PDB:1E4Q,
FT ECO:0007744|PDB:1FD3, ECO:0007744|PDB:1FD4,
FT ECO:0007744|PDB:1FQQ, ECO:0007744|PDB:6CS9"
FT DISULFID 38..53
FT /evidence="ECO:0000269|PubMed:10906336,
FT ECO:0000269|PubMed:11300761, ECO:0000269|PubMed:11714914,
FT ECO:0000269|PubMed:30050988, ECO:0007744|PDB:1E4Q,
FT ECO:0007744|PDB:1FD3, ECO:0007744|PDB:1FD4,
FT ECO:0007744|PDB:1FQQ, ECO:0007744|PDB:6CS9"
FT DISULFID 43..61
FT /evidence="ECO:0000269|PubMed:10906336,
FT ECO:0000269|PubMed:11300761, ECO:0000269|PubMed:11714914,
FT ECO:0000269|PubMed:30050988, ECO:0007744|PDB:1E4Q,
FT ECO:0007744|PDB:1FD3, ECO:0007744|PDB:1FD4,
FT ECO:0007744|PDB:1FQQ, ECO:0007744|PDB:6CS9"
FT MUTAGEN 33
FT /note="K->A: Loss of PIP2 binding and loss of liposomal
FT lysis activity. Decrease in fungal cell permeabilization.
FT Impaired antifungal activity."
FT /evidence="ECO:0000269|PubMed:30050988"
FT MUTAGEN 45
FT /note="R->A: Loss of PIP2 binding and loss of liposomal
FT lysis activity. Decrease in fungal cell permeabilization.
FT Impaired antifungal activity."
FT /evidence="ECO:0000269|PubMed:30050988"
FT MUTAGEN 46
FT /note="R->A: No impact on fungal cell permeabilization.
FT Impaired antifungal activity."
FT /evidence="ECO:0000269|PubMed:30050988"
FT MUTAGEN 47
FT /note="Y->A: No impact on fungal cell permeabilization. No
FT impact on antifungal activity."
FT /evidence="ECO:0000269|PubMed:30050988"
FT MUTAGEN 48
FT /note="K->A: Loss of PIP2 binding and reduced liposomal
FT lysis activity. Impaired antifungal activity. Decrease in
FT fungal cell permeabilization."
FT /evidence="ECO:0000269|PubMed:30050988"
FT MUTAGEN 59
FT /note="K->A: No impact on PIP binding and liposomal lysis
FT activity. Lack of antifungal activity. Lack of fungal cell
FT permeabilization."
FT /evidence="ECO:0000269|PubMed:30050988"
FT STRAND 25..27
FT /evidence="ECO:0007829|PDB:1FD4"
FT HELIX 28..33
FT /evidence="ECO:0007829|PDB:1FD3"
FT STRAND 37..41
FT /evidence="ECO:0007829|PDB:1FD3"
FT STRAND 48..52
FT /evidence="ECO:0007829|PDB:1FD3"
FT STRAND 53..55
FT /evidence="ECO:0007829|PDB:1E4Q"
FT STRAND 59..62
FT /evidence="ECO:0007829|PDB:1FD3"
SQ SEQUENCE 64 AA; 7038 MW; 05D6454CE7ACD10E CRC64;
MRVLYLLFSF LFIFLMPLPG VFGGIGDPVT CLKSGAICHP VFCPRRYKQI GTCGLPGTKC
CKKP
