{{short description|Family of proteins}} {{Pfam_box | Symbol = Defensin_beta | Name = Beta defensin | image =1ijv.png | width =200 | caption = | Pfam= PF00711 | InterPro= IPR001855 | SMART= | Prosite = | SCOP = 1bnb | TCDB = | OPM family= 54 | OPM protein= 1ut3 }}
'''Beta defensins ''' are a family of vertebrate defensins. The beta defensins are antimicrobial peptides implicated in the resistance of epithelial surfaces to microbial colonization.
Defensins are 2 to 6 kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses,<ref name="White_1995">{{cite journal | vauthors = White SH, Wimley WC, Selsted ME | title = Structure, function, and membrane integration of defensins | journal = Curr. Opin. Struct. Biol. | volume = 5 | issue = 4 | pages = 521–7 |date=August 1995 | pmid = 8528769 | doi = 10.1016/0959-440X(95)80038-7 | url = https://escholarship.org/uc/item/3z04k60j }}</ref> containing three pairs of intramolecular disulfide bonds. On the basis of their size and pattern of disulfide bonding, mammalian defensins are classified into alpha, beta and theta categories. Every mammalian species explored thus far has beta-defensins. In cows, as many as 13 beta-defensins exist in neutrophils. However, in other species, beta-defensins are more often produced by epithelial cells lining various organs (e.g. the epidermis, bronchial tree and genitourinary tract).
Human, rabbit and guinea-pig beta-defensins, as well as human beta-defensin-2 (hBD2), induce the activation and degranulation of mast cells, resulting in the release of histamine and prostaglandin D2.<ref name="pmid7628632">{{cite journal | vauthors = Bensch KW, Raida M, Mägert HJ, Schulz-Knappe P, Forssmann WG | title = hBD-1: a novel beta-defensin from human plasma | journal = FEBS Lett. | volume = 368 | issue = 2 | pages = 331–5 |date=July 1995 | pmid = 7628632 | doi = 10.1016/0014-5793(95)00687-5 | bibcode = 1995FEBSL.368..331B | s2cid = 84766207 | doi-access = free }}</ref>
== Genes==
β-defensins are coding for genes which impact the function of the innate immune system.<ref name="Hellgren_2011">{{cite journal | vauthors = Hellgren O, Sheldon BC | title = Locus-specific protocol for nine different innate immune genes (antimicrobial peptides: β-defensins) across passerine bird species reveals within-species coding variation and a case of trans-species polymorphisms | journal = Molecular Ecology Resources |date=July 2011 | volume = 11 | issue = 4| pages = 686–692 | doi = 10.1111/j.1755-0998.2011.02995.x | pmid = 21676198 | bibcode = 2011MolER..11..686H | s2cid = 12499158 }}</ref> These genes are responsible for production of antimicrobial peptides found in white blood cells such as macrophages, granulocytes and NK-cells, β-defensins are also found in epithelial cells.<ref name="pmid12949495">{{cite journal | author = Ganz T | title = Defensins: antimicrobial peptides of innate immunity | journal = Nat. Rev. Immunol. | volume = 3 | issue = 9 | pages = 710–20 |date=September 2003 | pmid = 12949495 | doi = 10.1038/nri1180 | s2cid = 3360031 }}</ref> Single-nucleotide polymorphisms (SNPs) are found in genes coding for β-defensins.<ref name=" Van_Dijk_2008">{{cite journal | vauthors = van Dijk A, Veldhuizen EJ, Haagsman HP | title = Avian defensins | journal = Vet. Immunol. Immunopathol. | volume = 124 | issue = 1–2 | pages = 1–18 |date=July 2008 | pmid = 18313763 | doi = 10.1016/j.vetimm.2007.12.006 | pmc = 7112556 }}</ref> The presences of SNPs are lower in the coding regions compared to non-coding regions.<ref name=" Van_Dijk_2008"/> The appearance of SNPs in the coding region will highly likely affecting the resistance against infections through changes in the protein sequences which will give rise to different biological functions.<ref name=" Van_Dijk_2008"/>
==Initiation==
Receptors such as toll-like receptors (TLR) and nod-like receptors (NLR) will activate the immune system by binding of ligands such as lipopolysaccharides and peptidoglycan.<ref name="Mogensen_2009">{{cite journal | author = Mogensen TH | title = Pathogen recognition and inflammatory signaling in innate immune defenses | journal = Clin. Microbiol. Rev. | volume = 22 | issue = 2 | pages = 240–73, Table of Contents |date=April 2009 | pmid = 19366914 | pmc = 2668232 | doi = 10.1128/CMR.00046-08 }}</ref> Toll-like receptors are expressed in intestinal epithelial cells <ref name=" Abreu MT_2010">{{cite journal | vauthors = Abreu MT | title = Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function | journal = Nat. Rev. Immunol.| volume = 10 | issue = 2 | pages = 131–44 |date=February 2010 | pmid = 20098461 | doi = 10.1038/nri2707| s2cid = 21789611 }}</ref> or antigen presenting cells (APCs) such as dendritic cells, B-lymphocytes and macrophages.<ref name=" Mogensen_2009"/> When the receptors are activated a cascade reaction will take place and substances such as cytokines and antimicrobial peptides<ref name=" Vora_2004">{{cite journal | vauthors = Vora P, Youdim A, Thomas LS, Fukata M, Tesfay SY, Lukasek K, Michelsen KS, Wada A, Hirayama T, Arditi M, Abreu MT | title = Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells | journal = J. Immunol.| volume = 173 | issue = 9 | pages = 5398–405 |date=November 2004 | pmid = 15494486 | doi = 10.4049/jimmunol.173.9.5398| doi-access = free }}</ref> will be released.<ref name=" Mogensen_2009"/>
==Function==
β-defensins are cationic and can therefore interact with the membrane of invading microbes, which are negative due to lipopolysaccharides (LPS) and lipoteichoic acid (LTA) found in the cell membrane.<ref name="White_1995"/> The peptides have higher affinity to the binding site compared to Ca2+ and Mg2+ ions.<ref name=" Van_Dijk_2008"/> The peptides will therefore exchange place with those ions, thus affecting the stability of the membrane.<ref name=" Van_Dijk_2008"/> The peptides have a greater size compared with the ions which cause changes in the membrane structure.<ref name=" Van_Dijk_2008"/> Due to changes in the electric potential, peptides will pass across the membrane and thus aggregate into dimers.<ref name="Sugiarto_2004">{{cite journal | vauthors = Sugiarto H, Yu PL | title = Avian antimicrobial peptides: the defense role of beta-defensins | journal = Biochem. Biophys. Res. Commun. | volume = 323 | issue = 3 | pages = 721–7 |date=October 2004 | pmid = 15381059 | doi = 10.1016/j.bbrc.2004.08.162 | bibcode = 2004BBRC..323..721S }}</ref> Pore complex will be created as a result of breaking the hydrogen bonds between the amino acids in the terminal end of the strands connecting defensins monomers.<ref name="Sugiarto_2004"/> Formation of pore complex will cause membrane depolarization and cell lysis.<ref name=" Van_Dijk_2008"/>
Defensins not only have the ability to strengthen the innate immune system but can also enhance the adaptive immune system by chemotaxis of monocytes, T-lymphocytes, dendritic cells and mast cells to the infection site.<ref name=" Van_Dijk_2008"/> Defensins will also improve the capacity of macrophage phagocytosis.<ref name=" Van_Dijk_2008"/>
==Avian β-defensins==
β-defensins are classified in three classes and avian β-defensins constitute for one of the classes.<ref name="Hellgren_2011"/> This division is based on Zhang's classification and both the length, the homology of the peptides and the gene structure are factors affecting the classification.<ref name="Sugiarto_2004"/>
Avian β-defensins are separated in avian heterophiles and non-heterophiles. Avian heterophiles can be divided into two sub-classes, depending on the number of present homologous residues in the genome.<ref name="Sugiarto_2004"/>
Avian heterophiles lack protective oxidative mechanisms, such as superoxide and myeloperoxidase, making non-oxidative mechanisms, such as lysosomes and cationic peptides, even more important.<ref name="Sugiarto_2004"/>
==Evolution==
β-defensins genes are found across the vertebrates, including mammals, reptiles, birds and fish.<ref name="Zhu 79–84">{{Cite journal|last1=Zhu|first1=Shunyi|last2=Gao|first2=Bin|date=January 2013|title=Evolutionary origin of β-defensins|url=http://dx.doi.org/10.1016/j.dci.2012.02.011|journal=Developmental & Comparative Immunology|volume=39|issue=1–2|pages=79–84|doi=10.1016/j.dci.2012.02.011|pmid=22369779|issn=0145-305X|url-access=subscription}}</ref> The fact that alpha and theta defensins are absent in older vertebrates, like birds and fishes, indicates that defensins must have evolved from the same ancestral gene coding for β-defensins.<ref name="pmid12734011">{{cite journal | vauthors = Semple CA, Rolfe M, Dorin JR | title = Duplication and selection in the evolution of primate beta-defensin genes | journal = Genome Biol. | volume = 4 | issue = 5 | article-number = R31 | year = 2003 | pmid = 12734011 | pmc = 156587 | doi = 10.1186/gb-2003-4-5-r31 | doi-access = free }}</ref> Indeed, these defensins of this superfamily are related to the 'big defensins' which are found in invertebrate animals, indicating even earlier origins.<ref name="Zhu 79–84"/>
In 2001, it was thought that β-defensins were similar to the ancestral defensin from a comparison of sequences of β-defensins, α-defensins and insect defensins.<ref name="pmid11486002">{{cite journal | vauthors = Hoover DM, Chertov O, Lubkowski J | title = The structure of human beta-defensin-1: new insights into structural properties of beta-defensins | journal = J. Biol. Chem. | volume = 276 | issue = 42 | pages = 39021–6 |date=October 2001 | pmid = 11486002 | doi = 10.1074/jbc.M103830200 | doi-access = free }}</ref> Subsequent structural analyses have suggested that the β-defensins, α-defensins, θ-defensins and big defensins share an evolutionary origin, but are separate to the defensins found in insects, fungi and plants.<ref>{{Cite journal|last1=Shafee|first1=Thomas M. A.|last2=Lay|first2=Fung T.|last3=Hulett|first3=Mark D.|last4=Anderson|first4=Marilyn A.|date=2016-06-13|title=The Defensins Consist of Two Independent, Convergent Protein Superfamilies|journal=Molecular Biology and Evolution|volume=33|issue=9|pages=2345–2356|doi=10.1093/molbev/msw106|pmid=27297472|issn=0737-4038|doi-access=free}}</ref>
In addition to other antimicrobial defensins, there are related defensin-like proteins with have evolved other functions. These include toxins found in snakes (e.g. crotamine), bearded lizards and platypus.<ref>{{Cite journal|last1=Whittington|first1=C. M.|last2=Papenfuss|first2=A. T.|last3=Bansal|first3=P.|last4=Torres|first4=A. M.|last5=Wong|first5=E. S.W.|last6=Deakin|first6=J. E.|last7=Graves|first7=T.|last8=Alsop|first8=A.|last9=Schatzkamer|first9=K.|last10=Kremitzki|first10=C.|last11=Ponting|first11=C. P.|date=2008-05-07|title=Defensins and the convergent evolution of platypus and reptile venom genes|journal=Genome Research|volume=18|issue=6|pages=986–994|doi=10.1101/gr.7149808|pmid=18463304|pmc=2413166|issn=1088-9051|doi-access=free}}</ref>
== History == The first beta-defensin discovered was Tracheal Antimicrobial Peptide, found in the bovine airway in 1991.<ref>{{cite journal|last1=Diamond|first1=G.|last2=Zasloff|first2=M.|last3=Eck|first3=H.|last4=Brasseur|first4=M.|last5=Maloy|first5=W.|last6=Bevins|first6=C.|title=Tracheal antimicrobial peptide, a novel cysteine-rich peptide from mammalian tracheal mucosa: Peptide isolation and cloning of a cDNA.|journal=Proc. Natl. Acad. Sci. USA|volume=88|pages=3952–3956|pmid=2023943|doi=10.1073/pnas.88.9.3952|pmc=51571|year=1991|issue=9|doi-access=free}}</ref> The first human beta-defensin, HBD1, was discovered in 1995,<ref name="pmid7628632"/> followed by the HBD2 in 1997.<ref name="pmid9441752">{{cite journal | vauthors = Harder J, Siebert R, Zhang Y, Matthiesen P, Christophers E, Schlegelberger B, Schröder JM | title = Mapping of the gene encoding human beta-defensin-2 (DEFB2) to chromosome region 8p22-p23.1 | journal = Genomics | volume = 46 | issue = 3 | pages = 472–5 |date=December 1997 | pmid = 9441752 | doi = 10.1006/geno.1997.5074 }}</ref>
==Human proteins containing this domain== DEFB1; DEFB103A; DEFB105A; DEFB105B; DEFB106; DEFB108B; DEFB109; DEFB110; DEFB111; DEFB114; DEFB130; DEFB136; DEFB4; SPAG11A;
==See also== * Defensin ** α-defensin ** β-defensin ** θ-defensin * Lingual antimicrobial peptide
==References== {{reflist|35em}}
==Further reading== {{refbegin}} * {{cite journal | vauthors = Liu L, Zhao C, Heng HH, Ganz T | title = The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry | journal = Genomics | volume = 43 | issue = 3 | pages = 316–20 |date=August 1997 | pmid = 9268634 | doi = 10.1006/geno.1997.4801 }} {{refend}}
Category:Defensins Category:Peripheral membrane proteins Category:Antimicrobial peptides