DEFA1 explained

Defensin, alpha 1 also known as human alpha defensin 1, human neutrophil peptide 1 (HNP-1) or neutrophil defensin 1 is a human protein that is encoded by the DEFA1 gene.^{[1] [2] [3]} Human alpha defensin 1 belongs to the alpha defensin family of antimicrobial peptides.

Function

Defensins are a family of microbicidal and cytotoxic peptides thought to be involved in host defense. They are abundant in the granules of neutrophils and also found in the epithelia of mucosal surfaces such as those of the intestine, respiratory tract, urinary tract, and vagina. Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif. Several alpha defensin genes are clustered on chromosome 8. The protein encoded by this gene, defensin, alpha 1, is found in the microbicidal granules of neutrophils and likely plays a role in phagocyte-mediated host defense. It differs from the defensins, alpha 2 and alpha 3 by only one amino acid.^[3]

Biosynthesis

HNPs are generated as 94 amino acids preproHNPs, which are co-translationally cleaved to 75 amino acids pro-peptides with a N-terminal prosegment having a negative charge that neutralizes the highly positively charged C terminal peptide. Processing of proHNPs occurs mainly in late promyelocytes, where the 75 amino acids proHNPs are cleaved to a 56 amino acids intermediate form and onward to 29-30 amino acids mature peptides designated HNPs.^{[4] [5]} Cationic 29-30 amino acids HNPs associate with the negatively charged proteoglycan serglycin and translocate to azurophil granules.^[6] At later stages of granulocytic differentiation in which HNP expression peaks (i.e. myelocytes and metamyelocytes), proHNPs are not cleaved, rendering the peptides overall neutral. This prevents binding to serglycin and most proHNP is accordingly secreted into the bone marrow plasma although some is retained in specific granules.^[7]

Further reading

• Lehrer RI, Lichtenstein AK, Ganz T . Defensins: antimicrobial and cytotoxic peptides of mammalian cells. . Annu. Rev. Immunol. . 11 . 105–28 . 1993 . 8476558 . 10.1146/annurev.iy.11.040193.000541 .
• Corda D, Di Girolamo M . Mono-ADP-ribosylation: a tool for modulating immune response and cell signaling. . Sci. STKE . 2002 . 163 . PE53 . 2003 . 12488509 . 10.1126/stke.2002.163.pe53 . 26277687 .
• Valore EV, Ganz T . Posttranslational processing of defensins in immature human myeloid cells. . Blood . 79 . 6 . 1538–44 . 1992 . 1339298 . 10.1182/blood.V79.6.1538.1538. free .
• 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. . Biochemistry . 31 . 46 . 11348–56 . 1992 . 1445872 . 10.1021/bi00161a012 .
• Pardi A, Zhang XL, Selsted ME . NMR studies of defensin antimicrobial peptides. 2. Three-dimensional structures of rabbit NP-2 and human HNP-1. . Biochemistry . 31 . 46 . 11357–64 . 1992 . 1445873 . 10.1021/bi00161a013 . etal.
• Hill CP, Yee J, Selsted ME, Eisenberg D . Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. . Science . 251 . 5000 . 1481–5 . 1991 . 2006422 . 10.1126/science.2006422 . 1991Sci...251.1481H .
• Bateman A, Singh A, Shustik C . The isolation and identification of multiple forms of the neutrophil granule peptides from human leukemic cells. . J. Biol. Chem. . 266 . 12 . 7524–30 . 1991 . 10.1016/S0021-9258(20)89478-2 . 2019582 . etal. free .
• Wagner MJ, Ge Y, Siciliano M, Wells DE . A hybrid cell mapping panel for regional localization of probes to human chromosome 8. . Genomics . 10 . 1 . 114–25 . 1991 . 2045096 . 10.1016/0888-7543(91)90491-V .
• Mitchell Kronenberg . Sparkes RS, Kronenberg M, Heinzmann C . Assignment of defensin gene(s) to human chromosome 8p23. . Genomics . 5 . 2 . 240–4 . 1989 . 2793180 . 10.1016/0888-7543(89)90052-9 . etal.
• Selsted ME, Harwig SS . Determination of the disulfide array in the human defensin HNP-2. A covalently cyclized peptide. . J. Biol. Chem. . 264 . 7 . 4003–7 . 1989 . 10.1016/S0021-9258(19)84952-9 . 2917986 . free .
• Wiedemann LM, Francis GE, Lamb RF . Differentiation stage-specific expression of a gene during granulopoiesis. . Leukemia . 3 . 3 . 227–34 . 1989 . 2918759 . etal.
• Ganz T, Selsted ME, Szklarek D . Defensins. Natural peptide antibiotics of human neutrophils. . J. Clin. Invest. . 76 . 4 . 1427–35 . 1985 . 2997278 . 10.1172/JCI112120 . 424093 . etal.
• Daher KA, Lehrer RI, Ganz T, Kronenberg M . Isolation and characterization of human defensin cDNA clones. . Proc. Natl. Acad. Sci. U.S.A. . 85 . 19 . 7327–31 . 1988 . 3174637 . 10.1073/pnas.85.19.7327 . 282179 . 1988PNAS...85.7327D . free .
• Mars WM, van Tuinen P, Drabkin HA . A myeloid-related sequence that localizes to human chromosome 8q21.1-22. . Blood . 71 . 6 . 1713–9 . 1988 . 3370315 . 10.1182/blood.V71.6.1713.1713. etal. free .
• Selsted ME, Harwig SS, Ganz T . Primary structures of three human neutrophil defensins. . J. Clin. Invest. . 76 . 4 . 1436–9 . 1985 . 4056036 . 10.1172/JCI112121 . 424095 . etal.
• Panyutich AV, Hiemstra PS, van Wetering S, Ganz T . Human neutrophil defensin and serpins form complexes and inactivate each other. . Am. J. Respir. Cell Mol. Biol. . 12 . 3 . 351–7 . 1995 . 7873202 . 10.1165/ajrcmb.12.3.7873202.
• Date Y, Nakazato M, Shiomi K . Localization of human neutrophil peptide (HNP) and its messenger RNA in neutrophil series. . Ann. Hematol. . 69 . 2 . 73–7 . 1994 . 8080882 . 10.1007/BF01698485 . 6651647 . etal.
• Linzmeier R, Michaelson D, Liu L, Ganz T . The structure of neutrophil defensin genes. . FEBS Lett. . 326 . 1–3 . 299–300 . 1993 . 8325384 . 10.1016/0014-5793(93)81813-F . 11526759 .
• Linzmeier R, Michaelson D, Liu L, Ganz T . The structure of neutrophil defensin genes . FEBS Lett. . 321 . 2–3 . 267–73 . 1993 . 8477861 . 10.1016/0014-5793(93)80122-B . 330693 . free .

Notes and References

1. Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM . Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes . J Neurosci . 17 . 5 . 1539–47 . Mar 1997 . 9030614 . 6573369. 10.1523/JNEUROSCI.17-05-01539.1997.
2. Aldred PM, Hollox EJ, Armour JA . Copy number polymorphism and expression level variation of the human alpha-defensin genes DEFA1 and DEFA3 . Hum Mol Genet . 14 . 14 . 2045–52 . Jul 2005 . 15944200 . 10.1093/hmg/ddi209 . free .
3. Web site: Entrez Gene: DEFA1 defensin, alpha 1.
4. Valore EV, Ganz T . Posttranslational processing of defensins in immature human myeloid cells. . Blood . 79 . 6 . 1538–44 . Mar 15, 1992 . 10.1182/blood.V79.6.1538.1538 . 1339298 . free .
5. Arnljots K, Sørensen O, Lollike K, Borregaard N . Timing, targeting and sorting of azurophil granule proteins in human myeloid cells. . Leukemia . 12 . 11 . 1789–95 . Nov 1998 . 9823955 . 10.1038/sj.leu.2401202 . free .
6. Glenthøj A, Cowland JB, Heegaard NH, Larsen MT, Borregaard N . Serglycin participates in retention of α-defensin in granules during myelopoiesis. . Blood . 118 . 16 . 4440–8 . Oct 20, 2011 . 21849484 . 10.1182/blood-2011-06-362947 . free .
7. Faurschou M, Kamp S, Cowland JB, Udby L, Johnsen AH, Calafat J, Winther H, Borregaard N . Prodefensins are matrix proteins of specific granules in human neutrophils. . Journal of Leukocyte Biology . 78 . 3 . 785–93 . Sep 2005 . 15944211 . 10.1189/jlb.1104688 . 14241958 .