DEF6_HUMAN
ID DEF6_HUMAN Reviewed; 100 AA.
AC Q01524; Q6EZF9;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1993, sequence version 1.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=Defensin-6;
DE AltName: Full=Defensin, alpha 6;
DE Flags: Precursor;
GN Name=DEFA6; Synonyms=DEF6;
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=Intestine;
RX PubMed=8417977; DOI=10.1016/0014-5793(93)81160-2;
RA Jones D.E., Bevins C.L.;
RT "Defensin-6 mRNA in human Paneth cells: implications for antimicrobial
RT peptides in host defense of the human bowel.";
RL FEBS Lett. 315:187-192(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RX PubMed=8626737; DOI=10.1074/jbc.271.8.4038;
RA Mallow E.B., Harris A., Salzman N., Russell J.P., Deberardinis R.J.,
RA Ruchelli E., Bevins C.L.;
RT "Human enteric defensins. Gene structure and developmental expression.";
RL J. Biol. Chem. 271:4038-4045(1996).
RN [3]
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 [4]
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 [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 PROTEIN SEQUENCE OF 20-23 AND 69-75, FUNCTION, SUBUNIT, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, PROTEOLYTIC CLEAVAGE AT ARG-68, AND MASS
RP SPECTROMETRY.
RX PubMed=27076903; DOI=10.1039/c5sc04194e;
RA Chairatana P., Chu H., Castillo P.A., Shen B., Bevins C.L., Nolan E.M.;
RT "Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a
RT Human alpha-Defensin Peptide.";
RL Chem. Sci. 7:1738-1752(2016).
RN [7]
RP FUNCTION, AND DISULFIDE BONDS.
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 [8]
RP FUNCTION, DISULFIDE BONDS, AND MUTAGENESIS OF PHE-70; VAL-90; ILE-93;
RP HIS-95 AND PHE-97.
RX PubMed=25158166; DOI=10.1021/ja5057906;
RA Chairatana P., Nolan E.M.;
RT "Molecular basis for self-assembly of a human host-defense peptide that
RT entraps bacterial pathogens.";
RL J. Am. Chem. Soc. 136:13267-13276(2014).
RN [9]
RP FUNCTION, MASS SPECTROMETRY, DISULFIDE BONDS, AND MUTAGENESIS OF HIS-95.
RX PubMed=25354318; DOI=10.1038/mi.2014.100;
RA Schroeder B.O., Ehmann D., Precht J.C., Castillo P.A., Kuechler R.,
RA Berger J., Schaller M., Stange E.F., Wehkamp J.;
RT "Paneth cell alpha-defensin 6 (HD-6) is an antimicrobial peptide.";
RL Mucosal Immunol. 8:661-671(2015).
RN [10]
RP FUNCTION, AND MUTAGENESIS OF PHE-70.
RX PubMed=28026958; DOI=10.1021/acs.biochem.6b01111;
RA Chairatana P., Chiang I.L., Nolan E.M.;
RT "Human alpha-Defensin 6 Self-Assembly Prevents Adhesion and Suppresses
RT Virulence Traits of Candida albicans.";
RL Biochemistry 56:1033-1041(2017).
RN [11]
RP SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=30808760; DOI=10.1073/pnas.1817376116;
RA Ehmann D., Wendler J., Koeninger L., Larsen I.S., Klag T., Berger J.,
RA Marette A., Schaller M., Stange E.F., Malek N.P., Jensen B.A.H.,
RA Wehkamp J.;
RT "Paneth cell alpha-defensins HD-5 and HD-6 display differential degradation
RT into active antimicrobial fragments.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:3746-3751(2019).
RN [12] {ECO:0007744|PDB:1ZMQ}
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 69-100, FUNCTION, SUBUNIT, AND
RP 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 [13] {ECO:0007744|PDB:3QTE}
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 69-100 OF MUTANT TRP-95,
RP FUNCTION, SUBUNIT, INTERACTION WITH Y.ENTEROCOLITICA INVASIN AND
RP S.TYPHIMURIUM FLIC/FLAGELLIN, DISULFIDE BONDS, AND MUTAGENESIS OF HIS-95.
RX PubMed=22722251; DOI=10.1126/science.1218831;
RA Chu H., Pazgier M., Jung G., Nuccio S.P., Castillo P.A., de Jong M.F.,
RA Winter M.G., Winter S.E., Wehkamp J., Shen B., Salzman N.H.,
RA Underwood M.A., Tsolis R.M., Young G.M., Lu W., Lehrer R.I., Baumler A.J.,
RA Bevins C.L.;
RT "Human alpha-defensin 6 promotes mucosal innate immunity through self-
RT assembled peptide nanonets.";
RL Science 337:477-481(2012).
CC -!- FUNCTION: Host-defense peptide that contributes to intestinal innate
CC immunity and mediates homeostasis at mucosal surfaces by forming
CC higher-order oligomers that capture bacteria and prevent microbial
CC invasion of the epithelium (PubMed:15616305, PubMed:25158166,
CC PubMed:25354318, PubMed:28026958, PubMed:17088326). After binding to
CC bacterial surface proteins, undergoes ordered self-assembly to form
CC fibril-like nanonets that surround and entangle bacteria and thereby
CC prevent bacterial invasion across the epithelial barrier
CC (PubMed:22722251). Entangles and agglutinates Gram-negative bacteria,
CC such as E.coli, S.typhimurium and Y.enterocolitica, and Gram-positive
CC bacteria such as L.monocytogenes, thereby protecting the intestine
CC against invasion by enteric bacterial pathogens (PubMed:27076903,
CC PubMed:25158166, PubMed:22722251). Blocks adhesion of C.albicans to
CC intestinal epithelial cells and thereby suppresses fungal invasion of
CC epithelial cells and biofilm formation (PubMed:28026958). Under
CC reducing conditions and in an acidic environment similar to the
CC intestinal milieu, exhibits inhibitory activity against anaerobic
CC bacteria such as B.adolescentis, L.acidophilus and B.breve, as well as
CC B.longum and S.thermophilus, possibly by leading to alterations in
CC bacterial cell envelope structures (PubMed:25354318). The disulfide-
CC linked oxidized form exhibits negligible antimicrobial activity against
CC Gram-negative and Gram-positive bacteria, as compared to the enteric
CC defensin DEFA5 (PubMed:15616305, PubMed:17088326).
CC {ECO:0000269|PubMed:15616305, ECO:0000269|PubMed:17088326,
CC ECO:0000269|PubMed:22722251, ECO:0000269|PubMed:25158166,
CC ECO:0000269|PubMed:25354318, ECO:0000269|PubMed:27076903,
CC ECO:0000269|PubMed:28026958}.
CC -!- SUBUNIT: Homodimer (PubMed:17088326, PubMed:27076903). Self-assembles
CC into higher-order oligomers termed nanonets, fibril-like structures
CC that entrap microbes (PubMed:22722251). Self-assembly into nanonets
CC seems to protect against proteolytic digestion in duodenal fluid
CC (PubMed:30808760). Interacts with Y.enterocolitica invasin and
CC S.typhimurium fliC/flagellin; the interaction creates an anchoring site
CC for progressive DEFA6 self-assembly into nanonets (PubMed:22722251).
CC {ECO:0000269|PubMed:17088326, ECO:0000269|PubMed:22722251,
CC ECO:0000269|PubMed:27076903, ECO:0000269|PubMed:30808760}.
CC -!- INTERACTION:
CC Q01524; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-10222451, EBI-744081;
CC Q01524; Q9UMX0: UBQLN1; NbExp=4; IntAct=EBI-10222451, EBI-741480;
CC Q01524; Q9UMX0-2: UBQLN1; NbExp=3; IntAct=EBI-10222451, EBI-10173939;
CC Q01524; Q9UHD9: UBQLN2; NbExp=6; IntAct=EBI-10222451, EBI-947187;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:27076903}.
CC Cytoplasmic vesicle, secretory vesicle {ECO:0000269|PubMed:27076903}.
CC Note=Stored as propeptide in secretory granules of small intestinal
CC Paneth cells and found in the ileum lumen as mature peptide.
CC {ECO:0000269|PubMed:27076903}.
CC -!- TISSUE SPECIFICITY: Expressed in Paneth cells of the small intestine
CC (at protein level). {ECO:0000269|PubMed:27076903,
CC ECO:0000269|PubMed:8417977, ECO:0000269|PubMed:8626737}.
CC -!- PTM: Proteolytically cleaved by trypsin at Arg-68; the propeptide is
CC stored in the tissue of the small intestine and the mature peptide is
CC found in the luminal fluid; cleavage may occur during or after release
CC into the lumen (PubMed:27076903). The N-terminal propeptide region
CC suppresses self-assembly and renders DEFA6 propeptide unable to
CC agglutinate bacteria and protect human epithelial cells from bacterial
CC invasion (PubMed:27076903). {ECO:0000269|PubMed:27076903}.
CC -!- PTM: Under reducing conditions, naturally present in the gut owing to
CC the low redox potential or enzymatically generated by the thioredoxin
CC system, the disulfide bridges are opened leading to a conformational
CC change of DEF6, thereby changing its antimicrobial spectrum
CC (PubMed:25354318). The reduced form exhibits inhibitory activity
CC against anaerobic bacteria, in contrast to the minimal antimicrobial
CC activity of the disulfide-linked oxidized form (PubMed:15616305,
CC PubMed:25354318, PubMed:17088326). The formation of higher-order
CC nanonets and bacterial entrapment is independent of the redox state
CC (PubMed:30808760). {ECO:0000269|PubMed:15616305,
CC ECO:0000269|PubMed:17088326, ECO:0000269|PubMed:25354318,
CC ECO:0000269|PubMed:30808760}.
CC -!- MASS SPECTROMETRY: [Defensin-6]: Mass=3709.9; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:27076903};
CC -!- MASS SPECTROMETRY: [Defensin-6]: Mass=3706.62; Method=MALDI;
CC Note=Oxidized form.; Evidence={ECO:0000269|PubMed:25354318};
CC -!- SIMILARITY: Belongs to the alpha-defensin family. {ECO:0000305}.
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DR EMBL; M98331; AAB59357.1; -; mRNA.
DR EMBL; U33317; AAC50382.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AF200455; AAT68876.1; -; Genomic_DNA.
DR EMBL; CH471153; EAW80484.1; -; Genomic_DNA.
DR EMBL; BC069667; AAH69667.1; -; mRNA.
DR EMBL; BC069710; AAH69710.1; -; mRNA.
DR EMBL; BC069728; AAH69728.1; -; mRNA.
DR EMBL; BC069769; AAH69769.1; -; mRNA.
DR EMBL; BC093951; AAH93951.1; -; mRNA.
DR EMBL; BC093953; AAH93953.1; -; mRNA.
DR CCDS; CCDS5960.1; -.
DR PIR; S27016; S27016.
DR RefSeq; NP_001917.1; NM_001926.3.
DR PDB; 1ZMQ; X-ray; 2.10 A; A/B/C/D=69-100.
DR PDB; 3QTE; X-ray; 1.95 A; A/B/C/D=69-100.
DR PDBsum; 1ZMQ; -.
DR PDBsum; 3QTE; -.
DR AlphaFoldDB; Q01524; -.
DR SMR; Q01524; -.
DR BioGRID; 108035; 61.
DR IntAct; Q01524; 17.
DR STRING; 9606.ENSP00000297436; -.
DR TCDB; 1.C.19.1.7; the defensin (defensin) family.
DR iPTMnet; Q01524; -.
DR PhosphoSitePlus; Q01524; -.
DR BioMuta; DEFA6; -.
DR DMDM; 399354; -.
DR jPOST; Q01524; -.
DR MassIVE; Q01524; -.
DR PaxDb; Q01524; -.
DR PeptideAtlas; Q01524; -.
DR PRIDE; Q01524; -.
DR ProteomicsDB; 57965; -.
DR Antibodypedia; 8201; 111 antibodies from 21 providers.
DR DNASU; 1671; -.
DR Ensembl; ENST00000297436.3; ENSP00000297436.2; ENSG00000164822.5.
DR Ensembl; ENST00000646187.2; ENSP00000494361.1; ENSG00000285136.2.
DR GeneID; 1671; -.
DR KEGG; hsa:1671; -.
DR MANE-Select; ENST00000297436.3; ENSP00000297436.2; NM_001926.4; NP_001917.1.
DR UCSC; uc003wqt.4; human.
DR CTD; 1671; -.
DR DisGeNET; 1671; -.
DR GeneCards; DEFA6; -.
DR HGNC; HGNC:2765; DEFA6.
DR HPA; ENSG00000164822; Tissue enriched (intestine).
DR MIM; 600471; gene.
DR neXtProt; NX_Q01524; -.
DR OpenTargets; ENSG00000164822; -.
DR PharmGKB; PA27242; -.
DR VEuPathDB; HostDB:ENSG00000164822; -.
DR eggNOG; ENOG502T2EX; Eukaryota.
DR GeneTree; ENSGT00940000153268; -.
DR HOGENOM; CLU_160803_3_0_1; -.
DR InParanoid; Q01524; -.
DR OMA; SCHFLER; -.
DR OrthoDB; 1550991at2759; -.
DR PhylomeDB; Q01524; -.
DR TreeFam; TF338414; -.
DR PathwayCommons; Q01524; -.
DR Reactome; R-HSA-1461973; Defensins.
DR Reactome; R-HSA-1462054; Alpha-defensins.
DR SignaLink; Q01524; -.
DR BioGRID-ORCS; 1671; 7 hits in 1027 CRISPR screens.
DR ChiTaRS; DEFA6; human.
DR EvolutionaryTrace; Q01524; -.
DR GeneWiki; DEFA6; -.
DR GenomeRNAi; 1671; -.
DR Pharos; Q01524; Tbio.
DR PRO; PR:Q01524; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q01524; protein.
DR Bgee; ENSG00000164822; Expressed in duodenum and 73 other tissues.
DR Genevisible; Q01524; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0030133; C:transport vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019731; P:antibacterial humoral response; IBA:GO_Central.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IBA:GO_Central.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IBA:GO_Central.
DR GO; GO:0050832; P:defense response to fungus; IEA:UniProtKB-KW.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IBA:GO_Central.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IBA:GO_Central.
DR GO; GO:0002227; P:innate immune response in mucosa; IBA:GO_Central.
DR GO; GO:0031640; P:killing of cells of another organism; IDA:UniProtKB.
DR GO; GO:0051673; P:membrane disruption in another organism; IBA:GO_Central.
DR InterPro; IPR016327; Alpha-defensin.
DR InterPro; IPR006081; Alpha-defensin_C.
DR InterPro; IPR002366; Alpha-defensin_propep.
DR InterPro; IPR006080; Defensin_beta/alpha.
DR PANTHER; PTHR11876; PTHR11876; 1.
DR Pfam; PF00323; Defensin_1; 1.
DR Pfam; PF00879; Defensin_propep; 1.
DR PIRSF; PIRSF001875; Alpha-defensin; 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; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT PROPEP 20..68
FT /evidence="ECO:0000269|PubMed:27076903"
FT /id="PRO_0000006790"
FT PEPTIDE 69..100
FT /note="Defensin-6"
FT /evidence="ECO:0000269|PubMed:27076903"
FT /id="PRO_0000006791"
FT DISULFID 72..99
FT /evidence="ECO:0000269|PubMed:17088326,
FT ECO:0000269|PubMed:22722251, ECO:0000269|PubMed:25158166,
FT ECO:0007744|PDB:1ZMQ, ECO:0007744|PDB:3QTE"
FT DISULFID 74..88
FT /evidence="ECO:0000269|PubMed:17088326,
FT ECO:0000269|PubMed:22722251, ECO:0000269|PubMed:25158166,
FT ECO:0007744|PDB:1ZMQ, ECO:0007744|PDB:3QTE"
FT DISULFID 78..98
FT /evidence="ECO:0000269|PubMed:17088326,
FT ECO:0000269|PubMed:22722251, ECO:0000269|PubMed:25158166,
FT ECO:0007744|PDB:1ZMQ, ECO:0007744|PDB:3QTE"
FT MUTAGEN 70
FT /note="F->A: Abrogates self-assembly to fibrils and
FT attenuates agglutination of bacteria and prevention of
FT L.monocytogenes invasion. Fails to block intestinal cell
FT adhesion and biofilm formation of C.albicans."
FT /evidence="ECO:0000269|PubMed:25158166,
FT ECO:0000269|PubMed:28026958"
FT MUTAGEN 90
FT /note="V->T: Perturbs self-assembly to fibrils and reduces
FT agglutination of bacteria."
FT /evidence="ECO:0000269|PubMed:25158166"
FT MUTAGEN 93
FT /note="I->T: Perturbs self-assembly to fibrils and reduces
FT agglutination of bacteria."
FT /evidence="ECO:0000269|PubMed:25158166"
FT MUTAGEN 95
FT /note="H->A: Does not impact fibril formation or
FT agglutination of bacteria."
FT /evidence="ECO:0000269|PubMed:25158166"
FT MUTAGEN 95
FT /note="H->W: Perturbs self-assembly to fibrils and reduces
FT agglutination of bacteria. Does not abolish antimicrobial
FT activity against B.adolescentis and formation of
FT extracellular net-like structures (under reducing
FT conditions)."
FT /evidence="ECO:0000269|PubMed:22722251,
FT ECO:0000269|PubMed:25158166, ECO:0000269|PubMed:25354318"
FT MUTAGEN 97
FT /note="F->A: Abrogates self-assembly to fibrils and
FT attenuates agglutination of bacteria and prevention of
FT L.monocytogenes invasion."
FT /evidence="ECO:0000269|PubMed:25158166"
FT STRAND 70..77
FT /evidence="ECO:0007829|PDB:1ZMQ"
FT STRAND 82..90
FT /evidence="ECO:0007829|PDB:1ZMQ"
FT STRAND 93..100
FT /evidence="ECO:0007829|PDB:1ZMQ"
SQ SEQUENCE 100 AA; 10975 MW; EDF77E033DDCE2D5 CRC64;
MRTLTILTAV LLVALQAKAE PLQAEDDPLQ AKAYEADAQE QRGANDQDFA VSFAEDASSS
LRALGSTRAF TCHCRRSCYS TEYSYGTCTV MGINHRFCCL
