DEFA5

DEFA5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1ZMP, 2LXZ, 2MIT, 3I5W, 4E82, 4E83, 4E86, 4RBW, 4RBX, 5CUM, 5CUJ, 5CUI
Identifiers
Aliases	DEFA5 , DEF5, HD-5, defensin alpha 5, alpha defensin 5
External IDs	OMIM: 600472; MGI: 3711900; HomoloGene: 128604; GeneCards: DEFA5; OMA:DEFA5 - orthologs
Gene location (Human) Chr. Chromosome 8 (human) [1] Band 8p23.1 Start 7,055,304 bp [1] End 7,056,739 bp [1]
Gene location (Mouse) Chr. Chromosome 8 (mouse) [2] Band 8 A2|8 Start 21,555,054 bp [2] End 21,556,012 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in duodenum gonad testicle appendix gastric mucosa right lung transverse colon lymph node rectum blood Top expressed in ileum jejunum duodenum embryo colon pancreas thymus esophagus liver stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity Cellular component Golgi lumen secretory granule lumen transport vesicle cytoplasmic vesicle extracellular region extracellular space Biological process defense response defense response to bacterium defense response to fungus antimicrobial humoral response antimicrobial humoral immune response mediated by antimicrobial peptide innate immune response positive regulation of membrane permeability killing of cells of other organism innate immune response in mucosa antibacterial humoral response defense response to Gram-negative bacterium defense response to Gram-positive bacterium membrane disruption in other organism cellular response to lipopolysaccharide Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1670 100041688 Ensembl ENSG00000164816 ENSG00000285251 ENSMUSG00000061845 UniProt Q01523 E9QLQ1 RefSeq (mRNA) NM_021010 NM_001177481 RefSeq (protein) NP_066290 NP_001170952 Location (UCSC) Chr 8: 7.06 – 7.06 Mb Chr 8: 21.56 – 21.56 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Defensin, alpha 5 (DEFA5) also known as human alpha defensin 5 (HD5) is a protein that in humans is encoded by the DEFA5 gene. ^{[5] [6]} DEFA5 is expressed in the Paneth cells of the ileum. ^[7]

Defensins are a family of microbicidal and cytotoxic peptides (antimicrobial peptides; AMP) that are involved in host defense, and help to maintain homeostasis of intestinal microbiota. DEFA5 is the main AMP that controls the enteric microbiota composition by selective killing of bacterial pathogens while preserving commensals. ^[8]

Structure

Defensins are small cationic peptides linked via three intra-molecular disulfide bridges, and contain six intra-molecular cysteine residues which form an unalterable and specific pattern of disulfide bridges which protects them from proteolysis and maintains function in the intestinal lumen. ^{[9] [10]} Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif.

Gene and tissue distribution

Several of the human alpha defensin genes appear to be clustered on chromosome 8. The protein encoded by this gene, α-defensin-5, is highly expressed in the secretory granules of Paneth cells of the ileum. ^[5]

Function

In addition to antimicrobial activity, inactivation and neutralization of several bacterial toxins, especially an inhibitory potency against Clostridioides difficile toxins were reported. ^{[11] [12]} α-defensin-5 is able to inhibit all three C. difficile toxins A (TcdA), B (TcdB) and CDT in the concentration-dependent manner, and inhibitory mechanism is different for each of them. TcdA and TcdB are inhibited by co-precipitation with DEFA5, and CDT is inhibited by the inactivation of the CDTb pore. ^[13] In addition to toxin neutralization, DEFA5 is capable to directly kill C. difficile cells by damaging the bacterial wall. ^[14]

References

1. ENSG00000285251 GRCh38: Ensembl release 89: ENSG00000164816, ENSG00000285251 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000061845 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: DEFA5 defensin, alpha 5, Paneth cell-specific".
6. Jones DE, Bevins CL (January 1993). "Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel". FEBS Letters. 315 (2): 187–92. doi: 10.1016/0014-5793(93)81160-2 . PMID   8417977. S2CID   45099115.
7. Zhao C, Wang I, Lehrer RI (November 1996). "Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells". FEBS Letters. 396 (2–3): 319–22. doi: 10.1016/0014-5793(96)01123-4 . PMID   8915011. S2CID   22367037.
8. Bevins CL, Salzman NH (May 2011). "Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis". Nature Reviews. Microbiology. 9 (5): 356–68. doi:10.1038/nrmicro2546. PMID   21423246. S2CID   39332656.
9. Ganz T, Lehrer RI (August 1994). "Defensins". Current Opinion in Immunology. 6 (4): 584–9. doi:10.1016/0952-7915(94)90145-7. PMID   7946046.
10. Selsted ME, Harwig SS (March 1989). "Determination of the disulfide array in the human defensin HNP-2. A covalently cyclized peptide". The Journal of Biological Chemistry. 264 (7): 4003–7. doi: 10.1016/S0021-9258(19)84952-9 . PMID   2917986.
11. Kim C, Slavinskaya Z, Merrill AR, Kaufmann SH (October 2006). "Human alpha-defensins neutralize toxins of the mono-ADP-ribosyltransferase family". The Biochemical Journal. 399 (2): 225–9. doi:10.1042/BJ20060425. PMC   1609915 . PMID   16817779.
12. Giesemann T, Guttenberg G, Aktories K (June 2008). "Human alpha-defensins inhibit Clostridium difficile toxin B". Gastroenterology. 134 (7): 2049–58. doi: 10.1053/j.gastro.2008.03.008 . PMID   18435932.
13. Korbmacher M, Fischer S, Landenberger M, Papatheodorou P, Aktories K, Barth H (2020). "Human α-Defensin-5 Efficiently Neutralizes Clostridioides difficile Toxins TcdA, TcdB, and CDT". Frontiers in Pharmacology. 11: 1204. doi: 10.3389/fphar.2020.01204 . PMC   7435013 . PMID   32903430.
14. Furci L, Baldan R, Bianchini V, Trovato A, Ossi C, Cichero P, Cirillo DM (March 2015). Morrison RP (ed.). "New role for human α-defensin 5 in the fight against hypervirulent Clostridium difficile strains". Infection and Immunity. 83 (3): 986–95. doi:10.1128/IAI.02955-14. PMC   4333456 . PMID   25547793.

Further reading

• Mallow EB, Harris A, Salzman N, Russell JP, DeBerardinis RJ, Ruchelli E, Bevins CL (February 1996). "Human enteric defensins. Gene structure and developmental expression". The Journal of Biological Chemistry. 271 (8): 4038–45. doi: 10.1074/jbc.271.8.4038 . PMID   8626737.
• Bevins CL, Jones DE, Dutra A, Schaffzin J, Muenke M (January 1996). "Human enteric defensin genes: chromosomal map position and a model for possible evolutionary relationships". Genomics. 31 (1): 95–106. doi:10.1006/geno.1996.0014. PMID   8808285.
• Porter EM, Liu L, Oren A, Anton PA, Ganz T (June 1997). "Localization of human intestinal defensin 5 in Paneth cell granules". Infection and Immunity. 65 (6): 2389–95. doi:10.1128/IAI.65.6.2389-2395.1997. PMC   175331 . PMID   9169779.
• Quayle AJ, Porter EM, Nussbaum AA, Wang YM, Brabec C, Yip KP, Mok SC (May 1998). "Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract". The American Journal of Pathology. 152 (5): 1247–58. PMC   1858596 . PMID   9588893.
• Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, et al. (June 2002). "Paneth cell trypsin is the processing enzyme for human defensin-5". Nature Immunology. 3 (6): 583–90. doi:10.1038/ni797. PMID   12021776. S2CID   22022089.
• Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL (April 2003). "Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin". Nature. 422 (6931): 522–6. Bibcode:2003Natur.422..522S. doi:10.1038/nature01520. PMID   12660734. S2CID   1096692.
• Szyk A, Wu Z, Tucker K, Yang D, Lu W, Lubkowski J (December 2006). "Crystal structures of human alpha-defensins HNP4, HD5, and HD6". Protein Science. 15 (12): 2749–60. doi:10.1110/ps.062336606. PMC   2242434 . PMID   17088326.
• Wu Z, Ericksen B, Tucker K, Lubkowski J, Lu W (September 2004). "Synthesis and characterization of human alpha-defensins 4-6". The Journal of Peptide Research. 64 (3): 118–25. doi:10.1111/j.1399-3011.2004.00179.x. PMID   15317502.
• de Leeuw E, Burks SR, Li X, Kao JP, Lu W (February 2007). "Structure-dependent functional properties of human defensin 5". FEBS Letters. 581 (3): 515–20. doi:10.1016/j.febslet.2006.12.036. PMC   1832120 . PMID   17250830.