ID DEF4_HUMAN Reviewed; 97 AA. AC P12838; Q6EZF8; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1993, sequence version 2. DT 04-NOV-2026, entry version 189. DE RecName: Full=Defensin alpha 4 {ECO:0000312|HGNC:HGNC:2763}; DE AltName: Full=Corticostatin HP-4 {ECO:0000303|PubMed:8469233}; DE AltName: Full=HNP-4 {ECO:0000303|PubMed:2500436}; DE Short=HP-4 {ECO:0000303|PubMed:2500436}; DE AltName: Full=Neutrophil defensin 4 {ECO:0000303|PubMed:15616305}; DE Flags: Precursor; GN Name=DEFA4 {ECO:0000312|HGNC:HGNC:2763}; GN Synonyms=DEF4 {ECO:0000312|HGNC:HGNC:2763}; 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], AND TISSUE SPECIFICITY. RC TISSUE=Bone marrow; RX PubMed=8469233; DOI=10.1210/mend.7.2.8469233; RA Palfree R.G.E., Sadro L.C., Solomon S.; RT "The gene encoding the human corticostatin HP-4 precursor contains a recent RT 86-base duplication and is located on chromosome 8."; RL Mol. Endocrinol. 7:199-205(1993). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Heart, and Lung; 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 [5] RP PROTEIN SEQUENCE OF 64-96, FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=2843187; DOI=10.1016/s0006-291x(88)81118-5; RA Singh A., Bateman A., Zhu Q., Shimasaki S., Esch F., Solomon S.; RT "Structure of a novel human granulocyte peptide with anti-ACTH activity."; RL Biochem. Biophys. Res. Commun. 155:524-529(1988). RN [6] RP PROTEIN SEQUENCE OF 64-96, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=2500436; DOI=10.1016/s0021-9258(18)60449-1; RA Wilde C.G., Griffith J.E., Marra M.N., Snable J.L., Scott R.W.; RT "Purification and characterization of human neutrophil peptide 4, a novel RT member of the defensin family."; RL J. Biol. Chem. 264:11200-11203(1989). RN [7] RP PROTEIN SEQUENCE OF 64-83, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=2501794; DOI=10.1073/pnas.86.14.5610; RA Gabay J.E., Scott R.W., Campanelli D., Griffith J., Wilde C., Marra M.N., RA Seeger M., Nathan C.F.; RT "Antibiotic proteins of human polymorphonuclear leukocytes."; RL Proc. Natl. Acad. Sci. U.S.A. 86:5610-5614(1989). RN [8] RP FUNCTION. RX PubMed=15317502; DOI=10.1111/j.1399-3011.2004.00179.x; RA Wu Z., Ericksen B., Tucker K., Lubkowski J., Lu W.; RT "Synthesis and characterization of human alpha-defensins 4-6."; RL J. Pept. Res. 64:118-125(2004). RN [9] RP FUNCTION. RX PubMed=15616305; DOI=10.1128/aac.49.1.269-275.2005; RA Ericksen B., Wu Z., Lu W., Lehrer R.I.; RT "Antibacterial activity and specificity of the six human alpha-defensins."; RL Antimicrob. Agents Chemother. 49:269-275(2005). RN [10] RP FUNCTION, AND INTERACTION WITH CD4 AND HIV-1 GP120. RX PubMed=15620707; DOI=10.1016/j.febslet.2004.11.062; RA Wu Z., Cocchi F., Gentles D., Ericksen B., Lubkowski J., Devico A., RA Lehrer R.I., Lu W.; RT "Human neutrophil alpha-defensin 4 inhibits HIV-1 infection in vitro."; RL FEBS Lett. 579:162-166(2005). RN [11] RP X-RAY CRYSTALLOGRAPHY, SUBUNIT, AND DISULFIDE BONDS. RX PubMed=17088326; DOI=10.1110/ps.062336606; RA Szyk A., Wu Z., Tucker K., Yang D., Lu W., Lubkowski J.; RT "Crystal structures of human alpha-defensins HNP4, HD5, and HD6."; RL Protein Sci. 15:2749-2760(2006). RN [12] {ECO:0007744|PDB:6DMM, ECO:0007744|PDB:6DMQ} RP X-RAY CRYSTALLOGRAPHY OF MUTANTS ALA-86 AND ALA-90, FUNCTION, SUBUNIT, RP INTERACTION WITH HIV-1 GP120 AND BACILLUS ANTHRACIS LEF, DISULFIDE BONDS, RP AND MUTAGENESIS OF CYS-65; CYS-67; LEU-69; PHE-71; CYS-72; ARG-73; ARG-74; RP ARG-78; CYS-82; PHE-89; TYR-91; CYS-92; CYS-93 AND ARG-95. RX PubMed=30658057; DOI=10.1016/j.bbamem.2019.01.007; RA Hu H., Di B., Tolbert W.D., Gohain N., Yuan W., Gao P., Ma B., He Q., RA Pazgier M., Zhao L., Lu W.; RT "Systematic mutational analysis of human neutrophil alpha-defensin HNP4."; RL Biochim. Biophys. Acta 1861:835-844(2019). RN [13] RP VARIANT [LARGE SCALE ANALYSIS] GLN-74. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: Host-defense peptide that has antimicrobial activity against CC Gram-negative bacteria, and to a lesser extent also against Gram- CC positive bacteria and fungi (PubMed:15317502, PubMed:15616305, CC PubMed:2500436, PubMed:2501794, PubMed:30658057). Exhibits CC antimicrobial activity against Gram-negative E.coli and E.aerogenes and CC Gram-positive S.faecalis, S.aureus and B.cereus and the yeast CC C.albicans (in vitro) (PubMed:15317502, PubMed:15616305, CC PubMed:17088326, PubMed:2500436, PubMed:2501794, PubMed:30658057). CC Interacts with pathogenic surface proteins and toxins, such as HIV-1 CC surface protein gp120 and B.anthracis anthrax lethal factor lef CC (PubMed:15620707, PubMed:30658057). Protects blood cells against CC infection with HIV-1 (in vitro) (PubMed:15620707). Inhibits enzymatic CC activity of B.anthracis lef/anthrax lethal factor (in vitro) CC (PubMed:30658057). Inhibits corticotropin (ACTH)-stimulated CC corticosterone production (in vitro) (PubMed:2843187). CC {ECO:0000269|PubMed:15317502, ECO:0000269|PubMed:15616305, CC ECO:0000269|PubMed:15620707, ECO:0000269|PubMed:17088326, CC ECO:0000269|PubMed:2500436, ECO:0000269|PubMed:2501794, CC ECO:0000269|PubMed:2843187, ECO:0000269|PubMed:30658057}. CC -!- SUBUNIT: Homodimer; homodimerization seems to be required for killing CC S.aureus, but not E.coli (PubMed:17088326, PubMed:30658057). Interacts CC with CD4 (PubMed:15620707). Interacts with HIV-1 surface protein gp120; CC homodimerization is required for the interaction (PubMed:15620707, CC PubMed:30658057). Interacts with Bacillus anthracis lef; CC homodimerization is required for the interaction (PubMed:30658057). CC {ECO:0000269|PubMed:15620707, ECO:0000269|PubMed:17088326, CC ECO:0000269|PubMed:30658057}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q01523}. CC Cytoplasmic vesicle, secretory vesicle {ECO:0000269|PubMed:2500436, CC ECO:0000269|PubMed:2501794}. Note=Stored as mature peptide in CC neutrophil granules. {ECO:0000269|PubMed:2500436}. CC -!- TISSUE SPECIFICITY: Expressed in neutrophils (at protein level) CC (PubMed:2500436, PubMed:2501794, PubMed:2843187). Expressed in bone CC marrow (PubMed:8469233). {ECO:0000269|PubMed:2500436, CC ECO:0000269|PubMed:2501794, ECO:0000269|PubMed:2843187, CC ECO:0000269|PubMed:8469233}. CC -!- PTM: The three-dimensional structure formed by the three intramolecular CC disulfide bridges is indispensable for effective bacterial killing. CC {ECO:0000269|PubMed:17088326, ECO:0000269|PubMed:30658057}. CC -!- SIMILARITY: Belongs to the alpha-defensin family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U18745; AAA64488.1; -; Genomic_DNA. DR EMBL; AF200455; AAT68877.1; -; Genomic_DNA. DR EMBL; CH471153; EAW80486.1; -; Genomic_DNA. DR EMBL; BC093959; AAH93959.1; -; mRNA. DR EMBL; BC106747; AAI06748.1; -; mRNA. DR EMBL; BC112091; AAI12092.1; -; mRNA. DR EMBL; X65977; CAA46792.1; -; mRNA. DR CCDS; CCDS5961.1; -. DR PIR; A47365; A47365. DR RefSeq; NP_001916.1; NM_001925.3. DR PDB; 1ZMM; X-ray; 1.60 A; A/B/C/D=64-96. DR PDB; 6DMM; X-ray; 1.67 A; A/B/C/D/E/F/G/H/I/J/K/L=64-96. DR PDB; 6DMQ; X-ray; 1.70 A; A/B/C/D/E/F/G/H=64-96. DR AlphaFoldDB; P12838; -. DR SMR; P12838; -. DR FunCoup; P12838; 217. DR IntAct; P12838; 1. DR STRING; 9606.ENSP00000297435; -. DR BioMuta; DEFA4; -. DR DMDM; 399352; -. DR MassIVE; P12838; -. DR PaxDb; 9606-ENSP00000297435; -. DR PeptideAtlas; P12838; -. DR ProteomicsDB; 52880; -. DR Antibodypedia; 22002; 144 antibodies from 25 providers. DR DNASU; 1669; -. DR Ensembl; ENST00000297435.3; ENSP00000297435.2; ENSG00000164821.5. DR Ensembl; ENST00000642522.2; ENSP00000493844.1; ENSG00000285318.2. DR GeneID; 1669; -. DR KEGG; hsa:1669; -. DR MANE-Select; ENST00000297435.3; ENSP00000297435.2; NM_001925.3; NP_001916.1. DR UCSC; uc003wqu.2; human. DR AGR; HGNC:2763; -. DR ClinPGx; PA27240; -. DR CTD; 1669; -. DR DisGeNET; 1669; -. DR GeneCards; DEFA4; -. DR HGNC; HGNC:2763; DEFA4. DR HPA; ENSG00000164821; Tissue enriched (bone). DR MIM; 601157; gene. DR OpenTargets; ENSG00000164821; -. DR VEuPathDB; HostDB:ENSG00000164821; -. DR eggNOG; ENOG502T2EX; Eukaryota. DR GeneTree; ENSGT00940000153268; -. DR HOGENOM; CLU_160803_0_0_1; -. DR InParanoid; P12838; -. DR OMA; AFHTQAE; -. DR OrthoDB; 9533897at2759; -. DR PAN-GO; P12838; 8 GO annotations based on evolutionary models. DR PhylomeDB; P12838; -. DR PathwayCommons; P12838; -. DR Reactome; R-HSA-1461973; Defensins. DR Reactome; R-HSA-1462054; Alpha-defensins. DR Reactome; R-HSA-6798695; Neutrophil degranulation. DR SignaLink; P12838; -. DR Agora; ENSG00000164821; -. DR BioGRID-ORCS; 1669; 21 hits in 1104 CRISPR screens. DR EvolutionaryTrace; P12838; -. DR GeneWiki; DEFA4; -. DR GenomeRNAi; 1669; -. DR Pharos; P12838; Tbio. DR PRO; PR:P12838; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; P12838; protein. DR Bgee; ENSG00000164821; Expressed in bone marrow and 78 other cell types or tissues. DR GO; GO:0042582; C:azurophil granule; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0035580; C:specific granule lumen; TAS:Reactome. DR GO; GO:0030133; C:transport vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0140911; F:pore-forming activity; IBA:GO_Central. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0019731; P:antibacterial humoral response; IDA:UniProtKB. DR GO; GO:0019732; P:antifungal humoral response; IDA:UniProtKB. DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IDA:UniProtKB. DR GO; GO:0019730; P:antimicrobial humoral response; IDA:UniProtKB. 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:0051673; P:disruption of plasma membrane integrity in another organism; IBA:GO_Central. DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB. DR InterPro; IPR016327; Alpha-defensin. DR InterPro; IPR006081; Alpha-defensin_C. DR InterPro; IPR002366; Alpha-defensin_N. DR InterPro; IPR006080; Beta/alpha-defensin_C. DR PANTHER; PTHR11876; ALPHA-DEFENSIN 1; 1. DR PANTHER; PTHR11876:SF23; DEFENSIN ALPHA 4; 1. DR Pfam; PF00323; Defensin_1; 1. DR Pfam; PF00879; Defensin_propep; 1. DR PIRSF; PIRSF001875; Alpha-defensin; 1. DR SMART; SM01418; Defensin_propep; 1. DR SMART; SM00048; DEFSN; 1. DR PROSITE; PS00269; DEFENSIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Antibiotic; Antimicrobial; Cytoplasmic vesicle; Defensin; KW Direct protein sequencing; Disulfide bond; Fungicide; KW Proteomics identification; Reference proteome; Secreted; Signal. FT SIGNAL 1..19 FT /evidence="ECO:0000255" FT PROPEP 20..63 FT /id="PRO_0000006781" FT PEPTIDE 64..96 FT /note="Defensin alpha 4" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="PRO_0000006782" FT PROPEP 97 FT /id="PRO_0000006783" FT DISULFID 65..93 FT /evidence="ECO:0000269|PubMed:17088326, FT ECO:0000269|PubMed:30658057, ECO:0007744|PDB:1ZMM, FT ECO:0007744|PDB:6DMM, ECO:0007744|PDB:6DMQ" FT DISULFID 67..82 FT /evidence="ECO:0000269|PubMed:17088326, FT ECO:0000269|PubMed:30658057, ECO:0007744|PDB:1ZMM, FT ECO:0007744|PDB:6DMM, ECO:0007744|PDB:6DMQ" FT DISULFID 72..92 FT /evidence="ECO:0000269|PubMed:17088326, FT ECO:0000269|PubMed:30658057, ECO:0007744|PDB:1ZMM, FT ECO:0007744|PDB:6DMM, ECO:0007744|PDB:6DMQ" FT VARIANT 8 FT /note="A -> P (in dbSNP:rs28661751)" FT /id="VAR_048861" FT VARIANT 8 FT /note="A -> V (in dbSNP:rs28488529)" FT /id="VAR_061132" FT VARIANT 74 FT /note="R -> Q (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs762433303)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036315" FT MUTAGEN 65 FT /note="C->A: Impairs bactericidal activity against E.coli FT and S.aureus; when associated with Ala-67, Ala-72, Ala-82, FT Ala-92 and Ala-93." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 67 FT /note="C->A: Impairs bactericidal activity against E.coli FT and S.aureus; when associated with Ala-65, Ala-72, Ala-82, FT Ala-92 and Ala-93." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 69 FT /note="L->A: Slight decrease in antibacterial activity FT against E.coli." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 71 FT /note="F->A: Decreased antibacterial activity against FT S.aureus." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 72 FT /note="C->A: Impairs bactericidal activity against E.coli FT and S.aureus; when associated with Ala-65, Ala-67, Ala-82, FT Ala-92 and Ala-93." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 73 FT /note="R->A: Decreased antibacterial activity against FT E.coli. Weakens interaction with B.anthracis lef and with FT HIV-1 gp120." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 74 FT /note="R->A: Decreased antibacterial activity against FT E.coli. Weakens interaction with B.anthracis lef and with FT HIV-1 gp120." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 78 FT /note="R->A: Decreased antibacterial activity against FT E.coli and S.aureus. Weakens interaction with B.anthracis FT lef and with HIV-1 gp120." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 82 FT /note="C->A: Impairs bactericidal activity against E.coli FT and S.aureus; when associated with Ala-65, Ala-67, Ala-72, FT Ala-92 and Ala-93." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 89 FT /note="F->A: Impaired homodimerization. Decreased FT antibacterial activity against S.aureus. Disrupts FT interaction with B.anthracis lef and with HIV-1 gp120." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 91 FT /note="Y->A: Slight decrease in antibacterial activity FT against E.coli and S.aureus." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 92 FT /note="C->A: Impairs bactericidal activity against E.coli FT and S.aureus; when associated with Ala-65, Ala-67, Ala-72, FT Ala-82 and Ala-93." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 93 FT /note="C->A: Impairs bactericidal activity against E.coli FT and S.aureus; when associated with Ala-65, Ala-67, Ala-72, FT Ala-82 and Ala-92." FT /evidence="ECO:0000269|PubMed:30658057" FT MUTAGEN 95 FT /note="R->A: Slight decrease in antibacterial activity FT against E.coli and S.aureus." FT /evidence="ECO:0000269|PubMed:30658057" FT STRAND 65..70 FT /evidence="ECO:0007829|PDB:1ZMM" FT STRAND 77..84 FT /evidence="ECO:0007829|PDB:1ZMM" FT STRAND 87..93 FT /evidence="ECO:0007829|PDB:1ZMM" SQ SEQUENCE 97 AA; 10504 MW; FE14334631EC2FD3 CRC64; MRIIALLAAI LLVALQVRAG PLQARGDEAP GQEQRGPEDQ DISISFAWDK SSALQVSGST RGMVCSCRLV FCRRTELRVG NCLIGGVSFT YCCTRVD //