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| image = PDB_1dfn_EBI.jpg
| image = PDB_1dfn_EBI.jpg
| width =
| width =
| caption = Structure of defensin HNP-3.<ref name="pmid2006422">{{cite journal |vauthors=Hill CP, Yee J, Selsted ME, Eisenberg D |title=Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization |journal=Science |volume=251 |issue=5000 |pages=1481–5 |date=March 1991 |pmid=2006422 |doi= 10.1126/science.2006422|url=}}</ref>
| caption = Structure of defensin HNP-3.<ref name="pmid2006422">{{cite journal |vauthors=Hill CP, Yee J, Selsted ME, Eisenberg D |title=Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization |journal=Science |volume=251 |issue=5000 |pages=1481–5 |date=March 1991 |pmid=2006422 |doi= 10.1126/science.2006422|bibcode=1991Sci...251.1481H }}</ref>
| Pfam= PF00323
| Pfam= PF00323
| InterPro= IPR006081
| InterPro= IPR006081
Line 11: Line 11:
| SCOP = 1dfn
| SCOP = 1dfn
| TCDB = 1.C.19
| TCDB = 1.C.19
| OPM family= 56
| OPM family= 54
| OPM protein= 1tv0
| OPM protein= 1tv0
| PDB=
| PDB=
{{PDB3|1tv0}}A:64-89 {{PDB3|1dfn}}A:66-94 {{PDB3|1zmi}}B:66-94
{{PDB3|1zmk}}A:66-94 {{PDB3|1zmh}}B:66-94
}}
}}
'''Alpha defensins''' are a family of mammalian [[defensin]] peptides of the alpha subfamily. They are also known as '''cryptdins''' and are produced within the [[Small intestine|small bowel]]. ''Cryptdin'' is a [[portmanteau]] of ''[[Crypts of Lieberkühn|crypt]]'' and ''defensin''.


⚫
Defensins are 2-6 kDa, [[cationic]], [[antimicrobial peptides]] active against many [[Gram-negative]] and [[Gram-positive]] [[bacteria]], [[fungi]], and [[enveloped virus]]es,<ref name="PUB00001093">{{cite journal |vauthors=Selsted ME, White SH, Wimley WC |title=Structure, function, and membrane integration of defensins |journal=Curr. Opin. Struct. Biol. |volume=5 |issue=4 |pages=521–527 |year=1995 |pmid=8528769 |doi=10.1016/0959-440X(95)80038-7}}</ref> containing three pairs of intramolecular [[disulfide]] bonds. On the basis of their size and pattern of [[disulfide bond]]ing, mammalian defensins are classified into alpha, beta and theta categories. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in [[neutrophil]]s, certain [[macrophage]] populations and [[Paneth cells]] of the small intestine.
'''Alpha defensins''' are a family of mammalian [[defensin]] peptides.


⚫
Defensins are produced constitutively and/or in response to microbial products or [[proinflammatory]] [[cytokines]]. Some defensins are also called [[corticostatin]]s because they inhibit [[corticotropin]]-stimulated [[corticosteroid]] production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is a consequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and [[hydrophobic]] regions, allows them to insert themselves into the [[phospholipid]] membranes so that their hydrophobic regions are buried within the [[lipid]] membrane interior and their charged (mostly cationic) regions interact with [[anionic]] phospholipid head groups and water. Subsequently, some defensins can aggregate to form 'channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process. Alpha defensins of the mouse bowel were historically called [[cryptdin]]s when first discovered.
⚫
Defensins are 2-6 kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses,<ref name="PUB00001093">{{cite journal |vauthors=Selsted ME, White SH, Wimley WC |title=Structure, function, and membrane integration of defensins |journal=Curr. Opin. Struct. Biol. |volume=5 |issue=4 |pages=521–527 |year=1995 |pmid=8528769 |doi=10.1016/0959-440X(95)80038-7}}</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. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine.


==Structure==
⚫
Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins (CS) because they inhibit corticotropin-stimulated corticosteroid production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is a consequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form 'channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process. Alpha defensins of the mouse bowel were historically called [[cryptdin]]s when first discovered.
⚫
HNP-1, HNP-2 and HNP-3 are encoded by two genes [[DEFA1]] and DEFA3 localized at [[chromosome 8]], location 8p23.1. [[DEFA1]] and [[DEFA3]] encode identical peptides except the conversion of the first amino acid from [[alanine]] in HNP-1 to [[aspartic acid]] in [[HNP-3]]; [[HNP-2]] is an [[N-terminal]]ly truncated iso-form lacking the first amino acid. Human neutrophil peptides are found in human [[atherosclerosis|atherosclerotic]] arteries, inhibit LDL metabolism and fibrinolysis and promote [[Lp(a)]] binding.<ref name="pmid16989837">{{cite journal |vauthors=Nassar H, Lavi E, Akkawi S, Bdeir K, Heyman SN, Raghunath PN, Tomaszewski J, Higazi AA | title = alpha-Defensin: link between inflammation and atherosclerosis | journal = Atherosclerosis | volume = 194 | issue = 2 | pages = 452–7 |date=Oct 2007 | pmid = 16989837 | doi =10.1016/j.atherosclerosis.2006.08.046 }}</ref>


Like other alpha-defensins, cryptdins are small, 32-36 amino acid long cationic peptides. They possess 6 conserved cysteines that form a [[tridisulfide]] array with an arrangement of [[cysteine]] pairings that typify alpha-defensins. Cryptdins also display a secondary and tertiary structure that is dominated by a three-stranded beta-sheet. The topology that arises from this structure is an [[amphipathic]] globular form in which the termini are paired opposite a pole including a cluster of cationic residues.<ref>{{cite journal | vauthors = Satchell DP, Sheynis T, Shirafuji Y, Kolusheva S, Ouellette AJ, Jelinek R | title = Interactions of mouse Paneth cell alpha-defensins and alpha-defensin precursors with membranes. Prosegment inhibition of peptide association with biomimetic membranes. | journal = J. Biol. Chem. | volume = 278 | issue = 16 | pages = 13838–46 | year = 2003 | pmid = 12574157 | doi = 10.1074/jbc.M212115200| doi-access = free }}</ref>
⚫
== Human defensins ==

⚫
Initially human alpha defensin peptides were isolated from the neutrophils and are thus called human neutrophil peptides.<ref name="pmid2997278">{{cite journal |vauthors=Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI | title = Defensins. Natural peptide antibiotics of human neutrophils | journal = J Clin Invest | volume = 76 | issue = 4 | pages = 1427–35 |date=Oct 1985 | pmid = 2997278 | pmc = 424093| doi =10.1172/JCI112120 }}</ref> Human neutrophil peptides are also known as α-[[defensins]].

⚫
Sequences of major human α-defensins:<ref name="pmid16909917">{{cite journal |vauthors=Bowdish DM, Davidson DJ, Hancock RE | title = Immunomodulatory Properties of Defensins and Cathelicidins | journal = CTMI | volume = 306 | issue = | pages = 27–66 | year = 2006 | month = | pmid = 16909917 | pmc = | doi = }}</ref>


⚫
Sequences of major human α-defensins:<ref name="pmid16909917">{{cite book |vauthors=Bowdish DM, Davidson DJ, Hancock RE | chapter = Immunomodulatory Properties of Defensins and Cathelicidins | title = Antimicrobial Peptides and Human Disease | journal = CTMI | volume = 306 | pages = 27–66 | year = 2006 | pmid = 16909917 | pmc =7121507 | doi = 10.1007/3-540-29916-5_2| series = Current Topics in Microbiology and Immunology | isbn = 978-3-540-29915-8 }}</ref>
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Genes encoding cryptdins are located on the proximal arm of mouse chromosome 8. They are similar to other enteric alpha-defensins genes in that they involve a two [[exon]] structure. The first exon encodes an N-terminal canonical [[signal peptide]] and proregion that is present in the cryptdin precursor. The processed, mature peptide is encoded by the second [[exon]] which is separated from the first [[exon]] by a ~500 bp [[intron]].<ref>{{cite journal | vauthors = Ouellette AJ, Darmoul D, Tran D, Huttner KM, Yuan J, Selsted ME| title = Peptide localization and gene structure of cryptdin 4, a differentially expressed mouse paneth cell alpha-defensin | journal = Infect. Immun. | volume = 67 | issue = 12 | pages = 6643–51 | year = 1999 | doi = 10.1128/IAI.67.12.6643-6651.1999 | pmid = 10569786 | pmc = 97078}}</ref>
⚫
HNP-1, HNP-2 and HNP-3 are encoded by two genes [[DEFA1]] and DEFA3 localized at chromosome 8, location 8p23.1. DEFA1 and DEFA3 encode identical peptides except the conversion of the first amino acid from alanine in HNP-1 to aspartic acid in HNP-3; HNP-2 is an N-terminally truncated iso-form lacking the first amino acid. Human neutrophil peptides are found in human atherosclerotic arteries, inhibit LDL metabolism and fibrinolysis and promote Lp(a) binding.<ref name="pmid16989837">{{cite journal |vauthors=Nassar H, Lavi E, Akkawi S, Bdeir K, Heyman SN, Raghunath PN, Tomaszewski J, Higazi AA | title = alpha-Defensin: link between inflammation and atherosclerosis | journal = Atherosclerosis | volume = 194 | issue = 2 | pages = 452–7 |date=Oct 2007 | pmid = 16989837 | pmc = | doi =10.1016/j.atherosclerosis.2006.08.046 }}</ref>

Biosynthesized as precursors possessing an anionic, N-terminal proregion, cryptdins are packaged into the apically directed secretory granules of Paneth cells. During this process and perhaps succeeding it, the precursors are cleaved by matrix metalloproteinase-7 (matrilysin; [[MMP-7]]). As a result of this proteolysis, the C-terminal mature form is released from the proregion.<ref>{{cite journal | vauthors = Wilson C, Ouellette A, Satchell D, Ayabe T, López-Boado Y, Stratman J, Hultgren S, Matrisian L, Parks W | title = Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. | journal = Science | volume = 286 | issue = 5437 | pages = 113–7 | year = 1999 | pmid = 10506557 | doi = 10.1126/science.286.5437.113}}</ref>

==Functional characteristics==
With the ability to kill gram-positive and gram-negative bacteria, fungi, spirochetes and some enveloped viruses, cryptdins are classified as broad-spectrum antimicrobial peptides. Although it is the least expressed of the six isoforms, cryptdin-4 is the most bactericidal. Procryptdins, however, are nonbactericidal and thus require degradation of the proregion by MMP-7 for activation. In response to bacterial antigens, Paneth cells release their secretory granules into the lumen of intestinal crypts. There, cryptdins, along with other antimicrobial peptides expressed by Paneth cells, contribute to enteric mucosal [[innate immunity]] by clearing the intestinal crypt of potential invading pathogens.<ref>{{cite journal | vauthors = Ayabe T, Satchell DP, Wilson CL, Parks WC,Selsted ME, Ouellette AJ | title = Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. | journal = Nat. Immunol. | volume = 1 | issue = 2 | pages = 113–8 | year = 2000 | pmid = 11248802 | doi = 10.1038/77783 | s2cid = 23204633 }}</ref>

⚫
== Human defensins ==
⚫
Initially human alpha defensin peptides were isolated from the neutrophils and are thus called human neutrophil peptides.<ref name="pmid2997278">{{cite journal |vauthors=Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI | title = Defensins. Natural peptide antibiotics of human neutrophils | journal = J Clin Invest | volume = 76 | issue = 4 | pages = 1427–35 |date=Oct 1985 | pmid = 2997278 | pmc = 424093| doi =10.1172/JCI112120 }}</ref> Human neutrophil peptides are also known as α-[[defensins]].


Human neutrophil-derived alpha-defensins (HNPs) are capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels
Human neutrophil-derived alpha-defensins (HNPs) are capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels
of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement activation argues that defensins upregulate innate host inflammatory defenses against microbial invasion.
of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement activation argues that defensins upregulate innate host inflammatory defenses against microbial invasion.


Human neutrophil defensin-1, -3, and -4 are elevated in nasal aspirates from children with naturally occurring adenovirus infection.<ref>V. S. Priyadharshini, F. Ramírez-Jiménez, M. Molina-Macip, et al., “Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection,” Canadian Respiratory Journal, vol. 2018, Article ID 1038593, 6 pages, 2018. https://doi.org/10.1155/2018/1038593.</ref>
In one small study, a significant increase in alpha-defensin levels was detected in [[T cell]] lysates of [[schizophrenia]] patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings.<!--
In one small study, a significant increase in alpha-defensin levels was detected in [[T cell]] lysates of [[schizophrenia]] patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings.<ref name="pmid18349140">{{cite journal |vauthors=Craddock RM, Huang JT, Jackson E |title=Increased alpha defensins as a blood marker for schizophrenia susceptibility |journal=[[Mol. Cell. Proteomics]] |volume= 7|issue= 7|pages= 1204–13|date=March 2008 |pmid=18349140 |doi=10.1074/mcp.M700459-MCP200 |display-authors=etal|doi-access=free }}</ref>


--><ref name="pmid18349140">{{cite journal |vauthors=Craddock RM, Huang JT, Jackson E |title=Increased alpha defensins as a blood marker for schizophrenia susceptibility |journal=[[Mol. Cell Proteomics]] |volume= 7|issue= 7|pages= 1204–13|date=March 2008 |pmid=18349140 |doi=10.1074/mcp.M700459-MCP200 |url=http://www.mcponline.org/cgi/pmidlookup?view=long&pmid=18349140|display-authors=etal}}</ref>
The [[Virtual Colony Count]] antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same [[microplate]].<ref name="pmid15616305">{{Cite journal|vauthors=Ericksen B, Wu Z, Lu W, Lehrer RI |title=Antibacterial Activity and Specificity of the Six Human α-Defensins |journal= Antimicrob. Agents Chemother. |volume=49 |issue= 1 |pages= 269–75 |year= 2005 |pmid= 15616305 |pmc= 538877 |doi= 10.1128/AAC.49.1.269-275.2005}}</ref>


⚫
===In human plasma===
The [[Virtual Colony Count]] antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same [[microplate]].<ref name="pmid15616305">{{Cite journal|vauthors=Ericksen B, Wu Z, Lu W, Lehrer RI |title=Antibacterial Activity and Specificity of the Six Human α-Defensins |journal= Antimicrob Agents Chemother. |volume=49 |issue= 1 |pages= 269–75 |year= 2005 |pmid= 15616305 |pmc= 538877 |doi= 10.1128/AAC.49.1.269-275.2005}}</ref>
⚫
HNPs have been extensively studied as plasma marker of a range of diseases such as atherosclerosis, rheumatic diseases,<ref>{{cite journal|last=Vordenbäumen|first=S|author2=Sander, O|author3= Bleck, E|author4= Schneider, M|author5= Fischer-Betz, R|title=Cardiovascular disease and serum defensin levels in systemic lupus erythematosus.|journal=Clinical and Experimental Rheumatology|date=May–Jun 2012|volume=30|issue=3|pages=364–70|pmid=22510487}}</ref> infections,<ref>{{cite journal|last=Panyutich|first=AV|author2=Panyutich, EA|author3= Krapivin, VA|author4= Baturevich, EA|author5= Ganz, T|title=Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis.|journal=The Journal of Laboratory and Clinical Medicine|date=August 1993|volume=122|issue=2|pages=202–7|pmid=8340706}}</ref> cancer,<ref>{{cite journal|last=Droin|first=N|author2=Hendra, JB|author3= Ducoroy, P|author4= Solary, E|title=Human defensins as cancer biomarkers and antitumour molecules.|journal=Journal of Proteomics|date=Aug 20, 2009|volume=72|issue=6|pages=918–27|pmid=19186224|doi=10.1016/j.jprot.2009.01.002}}</ref> preeclampsia,<ref>{{cite journal|last=Prieto|first=JA|author2=Panyutich, AV|author3= Heine, RP|title=Neutrophil activation in preeclampsia. Are defensins and lactoferrin elevated in preeclamptic patients?|journal=The Journal of Reproductive Medicine|date=January 1997|volume=42|issue=1|pages=29–32|pmid=9018642}}</ref> and schizophrenia.<ref>{{cite journal|last=Craddock|first=RM|author2=Huang, JT|author3=Jackson, E|author4=Harris, N|author5=Torrey, EF|author6=Herberth, M|author7= Bahn, S|title=Increased alpha-defensins as a blood marker for schizophrenia susceptibility.|journal=Molecular & Cellular Proteomics|date=July 2008|volume=7|issue=7|pages=1204–13|pmid=18349140|doi=10.1074/mcp.M700459-MCP200|doi-access=free}}</ref>

⚫
Antibodies directed against fully processed HNP-1 seem to have low affinity for the [[propeptides]], proHNPs. A recent study used antibodies directed against proHNPs to show that the predominant forms of alpha-defensins in plasma are in fact proHNPs.<ref>{{cite journal|last=Glenthøj|first=A|author2=Glenthøj, AJ|author3= Borregaard, N|title=ProHNPs are the principal α-defensins of human plasma.|journal=European Journal of Clinical Investigation|date=August 2013|volume=43|issue=8|pages=836–43|pmid=23718714|doi=10.1111/eci.12114|s2cid=205092943}}</ref>
⚫
==Alpha defensins in human plasma==
⚫
HNPs have been extensively studied as plasma marker of a range of diseases such as atherosclerosis, rheumatic diseases,<ref>{{cite journal|last=Vordenbäumen|first=S|author2=Sander, O|author3= Bleck, E|author4= Schneider, M|author5= Fischer-Betz, R|title=Cardiovascular disease and serum defensin levels in systemic lupus erythematosus.|journal=Clinical and experimental rheumatology|date=May–Jun 2012|volume=30|issue=3|pages=364–70|pmid=22510487}}</ref> infections,<ref>{{cite journal|last=Panyutich|first=AV|author2=Panyutich, EA|author3= Krapivin, VA|author4= Baturevich, EA|author5= Ganz, T|title=Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis.|journal=The Journal of laboratory and clinical medicine|date=August 1993|volume=122|issue=2|pages=202–7|pmid=8340706}}</ref> cancer,<ref>{{cite journal|last=Droin|first=N|author2=Hendra, JB|author3= Ducoroy, P|author4= Solary, E|title=Human defensins as cancer biomarkers and antitumour molecules.|journal=Journal of proteomics|date=Aug 20, 2009|volume=72|issue=6|pages=918–27|pmid=19186224|doi=10.1016/j.jprot.2009.01.002}}</ref> preeclampsia,<ref>{{cite journal|last=Prieto|first=JA|author2=Panyutich, AV|author3= Heine, RP|title=Neutrophil activation in preeclampsia. Are defensins and lactoferrin elevated in preeclamptic patients?|journal=The Journal of reproductive medicine|date=January 1997|volume=42|issue=1|pages=29–32|pmid=9018642}}</ref> and schizophrenia.<ref>{{cite journal|last=Craddock|first=RM|author2=Huang, JT|author3=Jackson, E|author4=Harris, N|author5=Torrey, EF|author6=Herberth, M|author7= Bahn, S|title=Increased alpha-defensins as a blood marker for schizophrenia susceptibility.|journal=Molecular & Cellular Proteomics|date=July 2008|volume=7|issue=7|pages=1204–13|pmid=18349140|doi=10.1074/mcp.M700459-MCP200}}</ref>
⚫
Antibodies directed against fully processed HNP-1 seem to have low affinity for the [[propeptides]], proHNPs. A recent study used antibodies directed against proHNPs to show that the predominant forms of alpha-defensins in plasma are in fact proHNPs.<ref>{{cite journal|last=Glenthøj|first=A|author2=Glenthøj, AJ|author3= Borregaard, N|title=ProHNPs are the principal α-defensins of human plasma.|journal=European journal of clinical investigation|date=August 2013|volume=43|issue=8|pages=836–43|pmid=23718714|doi=10.1111/eci.12114}}</ref>
ProHNPs are exclusively synthesized by neutrophil precursors in the bone marrow and appear to be very specific markers of [[granulopoiesis]].
ProHNPs are exclusively synthesized by neutrophil precursors in the bone marrow and appear to be very specific markers of [[granulopoiesis]].

==Gut expression==
Cryptdins are the protein products of a related family of highly polymorphic genes that are specifically expressed by mouse [[Paneth cells]] at the base of intestinal crypts.<ref>{{cite journal | author = Ouellette AJ | title = Paneth cells and innate immunity in the crypt microenvironment. | journal = Gastroenterology | volume = 113 | issue = 5 | pages = 1779–84 | year = 1997 | pmid = 9352884 | doi = 10.1053/gast.1997.v113.pm9352884| doi-access = free }}</ref> They were first characterized as products of [[cDNAs]] derived from mouse small intestinal RNA. To date, over 25 cryptdin-encoding transcripts have been described. Despite the expression of a relatively large number of cryptdin isoforms, only 6 cryptdins have been isolated at the protein level. Conventional nomenclature labels the isoforms cryptdins-1 through -6 in order of discovery. The primary structures of cryptdin isoforms are highly homologous. Most differences between the isoforms lie in the identity of residues at the N- and C-termini.


==See also==
==See also==
Line 71: Line 78:


==References==
==References==
{{Research help|Med}}
{{reflist}}
{{reflist}}


{{DEFAULTSORT:Alpha Defensin}}
{{DEFAULTSORT:Alpha Defensin}}
[[Category:Protein domains]]
[[Category:Defensins]]
[[Category:Peripheral membrane proteins]]
[[Category:Peripheral membrane proteins]]

Latest revision as of 12:49, 28 August 2024

Mammalian defensin
Structure of defensin HNP-3.[1]
Identifiers
SymbolDefensin_1
PfamPF00323
InterProIPR006081
PROSITEPDOC00242
SCOP21dfn / SCOPe / SUPFAM
TCDB1.C.19
OPM superfamily54
OPM protein1tv0
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. They are also known as cryptdins and are produced within the small bowel. Cryptdin is a portmanteau of crypt and defensin.

Defensins are 2-6 kDa, cationic, antimicrobial peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses,[2] 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. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine.

Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins because they inhibit corticotropin-stimulated corticosteroid production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is a consequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form 'channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process. Alpha defensins of the mouse bowel were historically called cryptdins when first discovered.

Structure

[edit]

HNP-1, HNP-2 and HNP-3 are encoded by two genes DEFA1 and DEFA3 localized at chromosome 8, location 8p23.1. DEFA1 and DEFA3 encode identical peptides except the conversion of the first amino acid from alanine in HNP-1 to aspartic acid in HNP-3; HNP-2 is an N-terminally truncated iso-form lacking the first amino acid. Human neutrophil peptides are found in human atherosclerotic arteries, inhibit LDL metabolism and fibrinolysis and promote Lp(a) binding.[3]

Like other alpha-defensins, cryptdins are small, 32-36 amino acid long cationic peptides. They possess 6 conserved cysteines that form a tridisulfide array with an arrangement of cysteine pairings that typify alpha-defensins. Cryptdins also display a secondary and tertiary structure that is dominated by a three-stranded beta-sheet. The topology that arises from this structure is an amphipathic globular form in which the termini are paired opposite a pole including a cluster of cationic residues.[4]

Sequences of major human α-defensins:[5]

Gene Aliases Peptide Sequence
DEFA1 HNP1 human neutrophil peptide 1 ACYCRIPACIAGERRYGTCIYQGRLWAFCC
HNP2 human neutrophil peptide 2   CYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA3 HNP3 human neutrophil peptide 3 DCYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA4 HNP4 human neutrophil peptide 4 VCSCRLVFCRRTELRVGNCLIGGVSFTYCCTRV
DEFA5 HD5 human defensin 5 ATCYCRHGRCATRESLSGVCEISGRLYRLCCR
DEFA6 HD6 human defensin 6 AFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL

Genes encoding cryptdins are located on the proximal arm of mouse chromosome 8. They are similar to other enteric alpha-defensins genes in that they involve a two exon structure. The first exon encodes an N-terminal canonical signal peptide and proregion that is present in the cryptdin precursor. The processed, mature peptide is encoded by the second exon which is separated from the first exon by a ~500 bp intron.[6]

Biosynthesized as precursors possessing an anionic, N-terminal proregion, cryptdins are packaged into the apically directed secretory granules of Paneth cells. During this process and perhaps succeeding it, the precursors are cleaved by matrix metalloproteinase-7 (matrilysin; MMP-7). As a result of this proteolysis, the C-terminal mature form is released from the proregion.[7]

Functional characteristics

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With the ability to kill gram-positive and gram-negative bacteria, fungi, spirochetes and some enveloped viruses, cryptdins are classified as broad-spectrum antimicrobial peptides. Although it is the least expressed of the six isoforms, cryptdin-4 is the most bactericidal. Procryptdins, however, are nonbactericidal and thus require degradation of the proregion by MMP-7 for activation. In response to bacterial antigens, Paneth cells release their secretory granules into the lumen of intestinal crypts. There, cryptdins, along with other antimicrobial peptides expressed by Paneth cells, contribute to enteric mucosal innate immunity by clearing the intestinal crypt of potential invading pathogens.[8]

Human defensins

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Initially human alpha defensin peptides were isolated from the neutrophils and are thus called human neutrophil peptides.[9] Human neutrophil peptides are also known as α-defensins.

Human neutrophil-derived alpha-defensins (HNPs) are capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement activation argues that defensins upregulate innate host inflammatory defenses against microbial invasion.

Human neutrophil defensin-1, -3, and -4 are elevated in nasal aspirates from children with naturally occurring adenovirus infection.[10] In one small study, a significant increase in alpha-defensin levels was detected in T cell lysates of schizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings.[11]

The Virtual Colony Count antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same microplate.[12]

In human plasma

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HNPs have been extensively studied as plasma marker of a range of diseases such as atherosclerosis, rheumatic diseases,[13] infections,[14] cancer,[15] preeclampsia,[16] and schizophrenia.[17] Antibodies directed against fully processed HNP-1 seem to have low affinity for the propeptides, proHNPs. A recent study used antibodies directed against proHNPs to show that the predominant forms of alpha-defensins in plasma are in fact proHNPs.[18] ProHNPs are exclusively synthesized by neutrophil precursors in the bone marrow and appear to be very specific markers of granulopoiesis.

Gut expression

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Cryptdins are the protein products of a related family of highly polymorphic genes that are specifically expressed by mouse Paneth cells at the base of intestinal crypts.[19] They were first characterized as products of cDNAs derived from mouse small intestinal RNA. To date, over 25 cryptdin-encoding transcripts have been described. Despite the expression of a relatively large number of cryptdin isoforms, only 6 cryptdins have been isolated at the protein level. Conventional nomenclature labels the isoforms cryptdins-1 through -6 in order of discovery. The primary structures of cryptdin isoforms are highly homologous. Most differences between the isoforms lie in the identity of residues at the N- and C-termini.

See also

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References

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  1. ^ Hill CP, Yee J, Selsted ME, Eisenberg D (March 1991). "Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization". Science. 251 (5000): 1481–5. Bibcode:1991Sci...251.1481H. doi:10.1126/science.2006422. PMID 2006422.
  2. ^ Selsted ME, White SH, Wimley WC (1995). "Structure, function, and membrane integration of defensins". Curr. Opin. Struct. Biol. 5 (4): 521–527. doi:10.1016/0959-440X(95)80038-7. PMID 8528769.
  3. ^ Nassar H, Lavi E, Akkawi S, Bdeir K, Heyman SN, Raghunath PN, Tomaszewski J, Higazi AA (Oct 2007). "alpha-Defensin: link between inflammation and atherosclerosis". Atherosclerosis. 194 (2): 452–7. doi:10.1016/j.atherosclerosis.2006.08.046. PMID 16989837.
  4. ^ Satchell DP, Sheynis T, Shirafuji Y, Kolusheva S, Ouellette AJ, Jelinek R (2003). "Interactions of mouse Paneth cell alpha-defensins and alpha-defensin precursors with membranes. Prosegment inhibition of peptide association with biomimetic membranes". J. Biol. Chem. 278 (16): 13838–46. doi:10.1074/jbc.M212115200. PMID 12574157.
  5. ^ Bowdish DM, Davidson DJ, Hancock RE (2006). "Immunomodulatory Properties of Defensins and Cathelicidins". Antimicrobial Peptides and Human Disease. Current Topics in Microbiology and Immunology. Vol. 306. pp. 27–66. doi:10.1007/3-540-29916-5_2. ISBN 978-3-540-29915-8. PMC 7121507. PMID 16909917. {{cite book}}: |journal= ignored (help)
  6. ^ Ouellette AJ, Darmoul D, Tran D, Huttner KM, Yuan J, Selsted ME (1999). "Peptide localization and gene structure of cryptdin 4, a differentially expressed mouse paneth cell alpha-defensin". Infect. Immun. 67 (12): 6643–51. doi:10.1128/IAI.67.12.6643-6651.1999. PMC 97078. PMID 10569786.
  7. ^ Wilson C, Ouellette A, Satchell D, Ayabe T, López-Boado Y, Stratman J, Hultgren S, Matrisian L, Parks W (1999). "Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense". Science. 286 (5437): 113–7. doi:10.1126/science.286.5437.113. PMID 10506557.
  8. ^ Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ (2000). "Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria". Nat. Immunol. 1 (2): 113–8. doi:10.1038/77783. PMID 11248802. S2CID 23204633.
  9. ^ Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI (Oct 1985). "Defensins. Natural peptide antibiotics of human neutrophils". J Clin Invest. 76 (4): 1427–35. doi:10.1172/JCI112120. PMC 424093. PMID 2997278.
  10. ^ V. S. Priyadharshini, F. Ramírez-Jiménez, M. Molina-Macip, et al., “Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection,” Canadian Respiratory Journal, vol. 2018, Article ID 1038593, 6 pages, 2018. https://doi.org/10.1155/2018/1038593.
  11. ^ Craddock RM, Huang JT, Jackson E, et al. (March 2008). "Increased alpha defensins as a blood marker for schizophrenia susceptibility". Mol. Cell. Proteomics. 7 (7): 1204–13. doi:10.1074/mcp.M700459-MCP200. PMID 18349140.
  12. ^ Ericksen B, Wu Z, Lu W, Lehrer RI (2005). "Antibacterial Activity and Specificity of the Six Human α-Defensins". Antimicrob. Agents Chemother. 49 (1): 269–75. doi:10.1128/AAC.49.1.269-275.2005. PMC 538877. PMID 15616305.
  13. ^ Vordenbäumen, S; Sander, O; Bleck, E; Schneider, M; Fischer-Betz, R (May–Jun 2012). "Cardiovascular disease and serum defensin levels in systemic lupus erythematosus". Clinical and Experimental Rheumatology. 30 (3): 364–70. PMID 22510487.
  14. ^ Panyutich, AV; Panyutich, EA; Krapivin, VA; Baturevich, EA; Ganz, T (August 1993). "Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis". The Journal of Laboratory and Clinical Medicine. 122 (2): 202–7. PMID 8340706.
  15. ^ Droin, N; Hendra, JB; Ducoroy, P; Solary, E (Aug 20, 2009). "Human defensins as cancer biomarkers and antitumour molecules". Journal of Proteomics. 72 (6): 918–27. doi:10.1016/j.jprot.2009.01.002. PMID 19186224.
  16. ^ Prieto, JA; Panyutich, AV; Heine, RP (January 1997). "Neutrophil activation in preeclampsia. Are defensins and lactoferrin elevated in preeclamptic patients?". The Journal of Reproductive Medicine. 42 (1): 29–32. PMID 9018642.
  17. ^ Craddock, RM; Huang, JT; Jackson, E; Harris, N; Torrey, EF; Herberth, M; Bahn, S (July 2008). "Increased alpha-defensins as a blood marker for schizophrenia susceptibility". Molecular & Cellular Proteomics. 7 (7): 1204–13. doi:10.1074/mcp.M700459-MCP200. PMID 18349140.
  18. ^ Glenthøj, A; Glenthøj, AJ; Borregaard, N (August 2013). "ProHNPs are the principal α-defensins of human plasma". European Journal of Clinical Investigation. 43 (8): 836–43. doi:10.1111/eci.12114. PMID 23718714. S2CID 205092943.
  19. ^ Ouellette AJ (1997). "Paneth cells and innate immunity in the crypt microenvironment". Gastroenterology. 113 (5): 1779–84. doi:10.1053/gast.1997.v113.pm9352884. PMID 9352884.
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