RBCC Red Blood Cell Collection

DEFA3 (DEF3) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Neutrophil defensin 3 (Defensin, alpha 3; HNP-3; HP-3; HP3; HP 3-56; Neutrophil defensin 2; HNP-2; HP-2; HP2; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P59666
ID DEF3_HUMAN Reviewed; 94 AA.
AC P59666; P11479; Q14125;
DT 30-APR-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-APR-2003, sequence version 1.
DT 22-JAN-2014, entry version 101.
DE RecName: Full=Neutrophil defensin 3;
DE AltName: Full=Defensin, alpha 3;
DE AltName: Full=HNP-3;
DE Short=HP-3;
DE Short=HP3;
DE Contains:
DE RecName: Full=HP 3-56;
DE Contains:
DE RecName: Full=Neutrophil defensin 2;
DE AltName: Full=HNP-2;
DE Short=HP-2;
DE Short=HP2;
DE Flags: Precursor;
GN Name=DEFA3; Synonyms=DEF3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3174637; DOI=10.1073/pnas.85.19.7327;
RA Daher K.A., Lehrer R.I., Ganz T., Kronenberg M.;
RT "Isolation and characterization of human defensin cDNA clones.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:7327-7331(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2918759;
RA Wiedemann L.M., Francis G.E., Lamb R.F., Burns J.H., Winnie J.N.,
RA McKenzie E.D., Birnie G.D.;
RT "Differentiation stage-specific expression of a gene during
RT granulopoiesis.";
RL Leukemia 3:227-234(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8477861; DOI=10.1016/0014-5793(93)80122-B;
RA Linzmeier R., Michaelson D., Liu L., Ganz T.;
RT "The structure of neutrophil defensin genes.";
RL FEBS Lett. 321:267-273(1993).
RN [4]
RP ERRATUM.
RX PubMed=8325384; DOI=10.1016/0014-5793(93)81813-F;
RA Linzmeier R., Michaelson D., Liu L., Ganz T.;
RL FEBS Lett. 326:299-300(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Spleen;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 65-94.
RX PubMed=4056036; DOI=10.1172/JCI112121;
RA Selsted M.E., Harwig S.S.L., Ganz T., Schilling J.W., Lehrer R.I.;
RT "Primary structures of three human neutrophil defensins.";
RL J. Clin. Invest. 76:1436-1439(1985).
RN [7]
RP DISULFIDE BONDS.
RX PubMed=2917986;
RA Selsted M.E., Harwig S.S.L.;
RT "Determination of the disulfide array in the human defensin HNP-2. A
RT covalently cyclized peptide.";
RL J. Biol. Chem. 264:4003-4007(1989).
RN [8]
RP PROTEOLYTIC PROCESSING.
RX PubMed=1339298;
RA Valore E.V., Ganz T.;
RT "Posttranslational processing of defensins in immature human myeloid
RT cells.";
RL Blood 79:1538-1544(1992).
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-
RT defensins.";
RL Antimicrob. Agents Chemother. 49:269-275(2005).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF DEFENSIN 3, SUBUNIT, AND
RP FUNCTION.
RX PubMed=2006422; DOI=10.1126/science.2006422;
RA Hill C.P., Yee J., Selsted M.E., Eisenberg D.;
RT "Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms
RT of membrane permeabilization.";
RL Science 251:1481-1485(1991).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.15 ANGSTROMS) OF 66-94, DISULFIDE BONDS, AND
RP FUNCTION.
RX PubMed=15894545; DOI=10.1074/jbc.M503084200;
RA Xie C., Prahl A., Ericksen B., Wu Z., Zeng P., Li X., Lu W.-Y.,
RA Lubkowski J., Lu W.;
RT "Reconstruction of the conserved beta-bulge in mammalian defensins
RT using D-amino acids.";
RL J. Biol. Chem. 280:32921-32929(2005).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 65-94, FUNCTION, AND SUBUNIT.
RX PubMed=17452329; DOI=10.1074/jbc.M611003200;
RA Zou G., de Leeuw E., Li C., Pazgier M., Li C., Zeng P., Lu W.-Y.,
RA Lubkowski J., Lu W.;
RT "Toward understanding the cationicity of defensins. Arg and Lys versus
RT their noncoded analogs.";
RL J. Biol. Chem. 282:19653-19665(2007).
CC -!- FUNCTION: Defensin 2 and defensin 3 have antibiotic, fungicide and
CC antiviral activities. Has antimicrobial activity against Gram-
CC negative and Gram-positive bacteria. Defensins are thought to kill
CC microbes by permeabilizing their plasma membrane.
CC -!- SUBUNIT: Dimer.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- SIMILARITY: Belongs to the alpha-defensin family.
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DR EMBL; M21131; AAA35753.2; -; mRNA.
DR EMBL; M23281; AAA52304.1; -; mRNA.
DR EMBL; L12691; AAB57722.1; -; Genomic_DNA.
DR EMBL; X13621; CAA31952.1; -; mRNA.
DR EMBL; BC027917; AAH27917.1; -; mRNA.
DR PIR; C40499; C40499.
DR RefSeq; NP_005208.1; NM_005217.3.
DR UniGene; Hs.654448; -.
DR PDB; 1DFN; X-ray; 1.90 A; A/B=65-94.
DR PDB; 1ZMH; X-ray; 1.50 A; A/B/C/D=66-94.
DR PDB; 1ZMI; X-ray; 1.15 A; A/B/C/D=66-94.
DR PDB; 1ZMK; X-ray; 1.30 A; A/B=66-94.
DR PDB; 2PM4; X-ray; 1.95 A; A/B=65-94.
DR PDB; 2PM5; X-ray; 2.40 A; A/B=65-94.
DR PDBsum; 1DFN; -.
DR PDBsum; 1ZMH; -.
DR PDBsum; 1ZMI; -.
DR PDBsum; 1ZMK; -.
DR PDBsum; 2PM4; -.
DR PDBsum; 2PM5; -.
DR ProteinModelPortal; P59666; -.
DR SMR; P59666; 66-94.
DR IntAct; P59666; 2.
DR MINT; MINT-1409240; -.
DR STRING; 9606.ENSP00000328359; -.
DR PhosphoSite; P59666; -.
DR DMDM; 30316323; -.
DR PaxDb; P59666; -.
DR PRIDE; P59666; -.
DR DNASU; 1668; -.
DR Ensembl; ENST00000327857; ENSP00000328359; ENSG00000239839.
DR GeneID; 1668; -.
DR KEGG; hsa:1668; -.
DR CTD; 1668; -.
DR GeneCards; GC08M006875; -.
DR HGNC; HGNC:2762; DEFA3.
DR HPA; HPA052517; -.
DR MIM; 604522; gene.
DR neXtProt; NX_P59666; -.
DR PharmGKB; PA27239; -.
DR eggNOG; NOG86943; -.
DR HOGENOM; HOG000233351; -.
DR HOVERGEN; HBG011703; -.
DR InParanoid; P59666; -.
DR KO; K05230; -.
DR OMA; QERDDEA; -.
DR OrthoDB; EOG75TMFQ; -.
DR PhylomeDB; P59666; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P59666; -.
DR GeneWiki; DEFA3; -.
DR GenomeRNAi; 1668; -.
DR NextBio; 6864; -.
DR PMAP-CutDB; P59666; -.
DR PRO; PR:P59666; -.
DR ArrayExpress; P59666; -.
DR Bgee; P59666; -.
DR CleanEx; HS_DEFA3; -.
DR Genevestigator; P59666; -.
DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0042742; P:defense response to bacterium; IEA:UniProtKB-KW.
DR GO; GO:0050832; P:defense response to fungus; IEA:UniProtKB-KW.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0031640; P:killing of cells of other organism; IEA:UniProtKB-KW.
DR InterPro; IPR016327; Alpha-defensin.
DR InterPro; IPR006080; Defensin_beta/neutrophil.
DR InterPro; IPR002366; Defensin_propep.
DR InterPro; IPR006081; Mammalian_defensins.
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; Antiviral defense;
KW Complete proteome; Defensin; Direct protein sequencing;
KW Disulfide bond; Fungicide; Reference proteome; Secreted; Signal.
FT SIGNAL 1 19
FT PROPEP 20 38
FT /FTId=PRO_0000006777.
FT CHAIN 39 94 HP 3-56.
FT /FTId=PRO_0000006778.
FT PEPTIDE 65 94 Neutrophil defensin 3.
FT /FTId=PRO_0000006779.
FT PEPTIDE 66 94 Neutrophil defensin 2.
FT /FTId=PRO_0000006780.
FT DISULFID 66 94
FT DISULFID 68 83
FT DISULFID 73 93
FT STRAND 67 71
FT STRAND 78 85
FT STRAND 88 94
SQ SEQUENCE 94 AA; 10245 MW; 0E0F8E957376C6AF CRC64;
MRTLAILAAI LLVALQAQAE PLQARADEVA AAPEQIAADI PEVVVSLAWD ESLAPKHPGS
RKNMDCYCRI PACIAGERRY GTCIYQGRLW AFCC
//

MIM 604522
*RECORD*
*FIELD* NO
604522
*FIELD* TI
*604522 DEFENSIN, ALPHA, 3; DEFA3
;;DEF3;;
HUMAN NEUTROPHIL PEPTIDE 3; HNP3
*FIELD* TX
read more
DESCRIPTION

See DEFA1 (125220) for background information on defensins. DEFA1 and
DEFA3 differ from each other only by their N-terminal amino acids (ala
and asp, respectively). DEFA2 is identical to both except that it lacks
this N-terminal amino acid.

GENE FUNCTION

Walker et al. (1986) described an anti-human immunodeficiency virus
(HIV) factor secreted by CD8 (see 186910) T cells from certain
HIV-1-infected individuals in a non-major histocompatibility complex
(MHC) class I-restricted and non-cell contact-dependent manner. The
factor, referred to as CAF (CD8 antiviral factor), is resistant to heat
and acid and is of low molecular mass. CAF is produced at relatively
higher levels by clinically stable HIV-1-infected patients, the
so-called long-term nonprogressors (LTNPs), but not by progressors.
Cocchi et al. (1995) determined that the beta chemokines CCL5 (187011),
CCL4 (182284), and CCL3 (182283) possess CAF-like activity, but only
against macrophage-tropic and not T-cell-tropic viral isolates, because
of their common usage of CCR5 (601373). Using a protein chip system and
mass spectrometric and protein database analyses, Zhang et al. (2002)
identified a cluster of three 3.3- to 3.5-kD proteins, DEFA1, DEFA2, and
DEFA3, secreted by LTNPs and most normal individuals, but not by
progressors. DEFA1-, DEFA2-, and DEFA3-specific antibodies depleted
antiviral activity in a dose-dependent manner, particularly against
viruses using CXCR4 (162643) rather than CCR5 as a coreceptor. Addition
of synthetic or purified natural defensins inhibited HIV-1 replication
in vitro. Flow cytometric analysis determined that in addition to
neutrophils, a small population of CD8-positive T lymphocytes harbor and
secrete DEFA1, DEFA2, and DEFA3. Zhang et al. (2002) proposed that these
defensins account for much of the anti-HIV-1 activity of CAF that is not
attributable to beta chemokines.

Chang et al. (2003) investigated whether DEFAs, particularly DEFA1,
contribute to CAF-mediated inhibition of HIV-1 transcription. They found
that DEFA1 inhibited HIV-1 infection following viral entry, but that the
DEFAs were not involved in the inhibition of HIV-1 gene expression and
long terminal repeat activation attributed to CAF derived from
herpesvirus saimiri-transformed CD8-positive cells.

Independently, Mackewicz et al. (2003) showed that DEFA1, DEFA2, and
DEFA3 exhibit anti-HIV activity by directly inactivating HIV particles
and by reducing the ability of CD4-positive T lymphocytes to replicate
the virus. Immunocytochemical and RT-PCR analysis detected expression of
DEFAs in neutrophils and monocytes, but not in CD8-positive T cells.
Antibodies specific for the DEFAs did not block the antiviral activity
of CAF-active CD8-positive cell culture fluids, indicating that,
although DEFAs possess anti-HIV effects, they are distinct from CAF.

In a retraction based upon RT-PCR analysis and careful dissection of
their cell culture system, Zhang et al. (2002) concluded that their
initial interpretation of a possible CD8-positive T-lymphocyte source
for DEFAs was incorrect. CAF activity from CD8-positive cells, in the
absence of contaminating neutrophil feeder cells, could not be
attributed to DEFAs. However, neutrophil-derived DEFAs did have potent
anti-HIV-1 activity, regardless of viral strain or target cell.

Anthrax lethal toxin, a combination of the bacterium's lethal factor and
protective antigen proteins, plays a major role in anthrax pathogenesis.
Kim et al. (2005) showed that HNP1, HNP2, and HNP3 could neutralize
anthrax lethal toxin activity and protect murine macrophages in vitro
and adult mice. They proposed that these defensins have potential for
immunotherapy of anthrax.

By screening for compounds that inhibited infection by human
papillomavirus (HPV) using pseudoviruses capable of infecting HeLa
cells, Buck et al. (2006) found that DEFA1, DEFA2, DEFA3, and DEFA5
(600472) were potent antagonists of both mucosal and cutaneous HPVs.
DEFA4 (601157) was less active, and DEFA6 (600471), DEFB1 (602056), and
DEFB2 (DEFB4; 602215) showed little to no activity. DEFA5 was
particularly active against sexually transmitted HPV types. DEFA1 and
DEFA5 also inhibited HPV-mediated transduction of other cell types.
Immunofluorescent confocal microscopy revealed that inhibition occurred
at the level of virion escape from endocytic vesicles, but not at virion
binding or internalization, and pseudoviruses remained susceptible for
many hours after initial binding to cells. Mutant DEFA2 peptides with
lower antibacterial activity that wildtype DEFA2 retained anti-HPV
effects, suggesting that its incorporation in a topical microbicide
could augment innate defenses in the vaginal tract without disrupting
the normal flora.

MAPPING

By Southern blot analysis of somatic cell hybrids, Mars et al. (1995)
established that there are at least 2 defensin genes on chromosome 8.
Sequencing established that one of these genes encodes DEFA1 and another
encodes DEFA3.

MOLECULAR GENETICS

Aldred et al. (2005) identified variation in both number and position of
DEFA1 and DEFA3 genes in arrays of 19-kb tandem repeats on chromosome
8p23.1, so that the DEFA1 and DEFA3 genes appeared to be interchangeable
variant cassettes within tandem gene arrays. The total number of gene
copies per diploid genome varied between 4 and 11 in a sample of 111
control individuals from the UK, with approximately 10% of people
lacking DEFA3 completely. DEFA1 appeared to be at high copy number in
all great apes studied; at 1 variable site in the repeat unit, both
variants have persisted in humans, chimpanzees, and gorillas since their
divergence. Analysis of expression levels in human white blood cells
showed a clear correlation between the relative proportions of
DEFA1:DEFA3 mRNA and corresponding gene numbers. However, there was no
relationship between total (DEFA1+DEFA3) mRNA levels and total gene copy
number, suggesting the superimposed influence of trans-acting factors.
Due to the persistence of DEFA1 at high copy number in other apes,
Aldred et al. (2005) suggested an alternative model for the early stages
of the evolution of novel genes by duplication and divergence.

*FIELD* RF
1. Aldred, P. M. R.; Hollox, E. J.; Armour, J. A. L.: Copy number
polymorphism and expression level variation of the human alpha-defensin
genes DEFA1 and DEFA3. Hum. Molec. Genet. 14: 2045-2052, 2005.

2. Buck, C. B.; Day, P. M.; Thompson, C. D.; Lubkowski, J.; Lu, W.;
Lowy, D. R.; Schiller, J. T.: Human alpha-defensins block papillomavirus
infection. Proc. Nat. Acad. Sci. 103: 1516-1521, 2006.

3. Chang, T. L.-Y.; Francois, F.; Mosoian, A.; Klotman, M. E.: CAF-mediated
human immunodeficiency virus (HIV) type 1 transcriptional inhibition
is distinct from alpha-defensin-1 HIV inhibition. J. Virol. 77:
6777-6784, 2003.

4. Cocchi, F.; DeVico, A. L.; Garzino-Demo, A.; Arya, S. K.; Gallo,
R. C.; Lusso, P.: Identification of RANTES, MIP-1-alpha and MIP-1-beta
as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:
1811-1815, 1995.

5. Kim, C.; Gajendran, N.; Mittrucker, H.-W.; Weiwad, M.; Song, Y.-H.;
Hurwitz, R.; Wilmanns, M.; Fischer, G.; Kaufmann, S. H. E.: Human
alpha-defensins neutralize anthrax lethal toxin and protect against
its fatal consequences. Proc. Nat. Acad. Sci. 102: 4830-4835, 2005.

6. Mackewicz, C. E.; Yuan, J.; Tran, P.; Diaz, L.; Mack, E.; Selsted,
M. E.; Levy, J. A.: Alpha-defensins can have anti-HIV activity but
are not CD8 cell anti-HIV factors. AIDS 17: F23-F32, 2003. Note:
Erratum: AIDS 17: F31 only, 2003.

7. Mars, W. M.; Patmasiriwat, P.; Maity, T.; Huff, V.; Weil, M. M.;
Saunders, G. F.: Inheritance of unequal numbers of the genes encoding
the human neutrophil defensins HP-1 and HP-3. J. Biol. Chem. 270:
30371-30376, 1995.

8. Walker, C. M.; Moody, D. J.; Stites, D. P.; Levy, J. A.: CD8+
lymphocytes can control HIV infection in vitro by suppressing virus
replication. Science 234: 1563-1566, 1986.

9. Zhang, L.; Yu, W.; He, T.; Yu, J.; Caffrey, R. E.; Dalmasso, E.
A.; Fu, S.; Pham, T.; Mei, J.; Ho, J. J.; Zhang, W.; Lopez, P.; Ho,
D. D.: Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1
activity of CD8 antiviral factor. Science 298: 995-1000, 2002. Note:
Retraction: Science 303: 467 only, 2004.

*FIELD* CN
George E. Tiller - updated: 11/18/2008
Paul J. Converse - updated: 10/20/2006
Paul J. Converse - updated: 3/24/2006
Paul J. Converse - updated: 2/13/2004
Matthew B. Gross - updated: 2/5/2004
Paul J. Converse - updated: 2/5/2004
Paul J. Converse - updated: 11/6/2002

*FIELD* CD
Paul J. Converse: 2/8/2000

*FIELD* ED
terry: 03/14/2013
wwang: 11/18/2008
mgross: 10/20/2006
mgross: 3/30/2006
terry: 3/24/2006
mgross: 2/13/2004
mgross: 2/5/2004
mgross: 11/6/2002
joanna: 12/29/2000
carol: 2/9/2000