Summary: Mammalian defensin

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Alpha defensin Edit Wikipedia article

Mammalian defensin

Structure of defensin HNP-3.^[1]

Identifiers

Symbol

Defensin_1

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Alpha defensins are a family of mammalian defensin peptides.

Defensins are 2-6 kDa, cationic, microbicidal 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 (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; other s 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.

[edit] Human defensins

Initially human alpha defensin peptides were isolated from the neutrophils and are thus called human neutrophil peptides.^[3] Human neutrophil peptides are also known as α-defensins.

Sequences of major human α-defensins:^[4]

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

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.^[5]

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.

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.^[6]

The Virtual Colony Count antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same microplate.^[7]

[edit] References

^ 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. doi:10.1126/science.2006422. PMID 2006422.
^ 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.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC424093/.
^ Bowdish D M E, Davidson D J, Hancock R E W (2006). "Immunomodulatory Properties of Defensins and Cathelicidins". CTMI 306: 27–66. PMID 16909917.
^ 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.
^ 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. doi:10.1074/mcp.M700459-MCP200. PMID 18349140. http://www.mcponline.org/cgi/pmidlookup?view=long&pmid=18349140.
^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC538877/.

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External database links

HOMSTRAD:	DEFSN
PANDIT:	PF00323
PROSITE:	PDOC00242
Pseudofam:	PF00323
SCOP:	1dfn
SYSTERS:	Defensin_1
Transporter classification:	1.C.19

This tab holds annotation information from the InterPro database.

InterPro entry IPR006081

Defensins are 2-6 kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses [PUBMED:8528769], containing three pairs of intramolecular disulphide bonds. On the basis of their size and pattern of disulphide 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 (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.

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 defences against microbial invasion.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Cellular component	extracellular region (GO:0005576)
Biological process	defense response (GO:0006952)

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Defensin (CL0075), which contains the following 7 members:

Defensin_1 Defensin_3 Defensin_4 Defensin_beta Defensin_beta_2 Defensin_big Toxin_4

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

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full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (11)	Full (136)	Representative proteomes				NCBI (185)	Meta (0)
	Seed (11)	Full (136)	RP15 (5)	RP35 (5)	RP55 (8)	RP75 (56)	NCBI (185)	Meta (0)
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¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (11)	Full (136)	Representative proteomes				NCBI (185)	Meta (0)
	Seed (11)	Full (136)	RP15 (5)	RP35 (5)	RP55 (8)	RP75 (56)	NCBI (185)	Meta (0)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (11)	Full (136)	Representative proteomes				NCBI (185)	Meta (0)
	Seed (11)	Full (136)	RP15 (5)	RP35 (5)	RP55 (8)	RP75 (56)	NCBI (185)	Meta (0)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Prosite

Previous IDs:

defensins;

Type:

Domain

Author:

Finn RD

Number in seed:

11

Number in full:

136

Average length of the domain:

29.00 aa

Average identity of full alignment:

47 %

Average coverage of the sequence by the domain:

32.72 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	21.4	21.4
Trusted cut-off	21.6	21.5
Noise cut-off	20.1	21.1

Model length:

29

Family (HMM) version:

14

Download:

download the raw HMM for this family

Species distribution

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How the sunburst is generated

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Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

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Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

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Interactions

There is 1 interaction for this family. More...

Defensin_1

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Defensin_1 domain has been found. There are 60 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: Defensin_1 (PF00323)

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Summary: Mammalian defensin

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Alpha defensin Edit Wikipedia article

[edit] Human defensins

[edit] References

Mammalian defensin Provide feedback

External database links

InterPro entry IPR006081

Gene Ontology

Domain organisation

Pfam Clan

Alignments

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Format an alignment

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Curation and family details

Curation

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Species distribution

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Interactions

Structures