Summary: Interleukin 4

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Interleukin 4 Edit Wikipedia article

Interleukin 4

Crystal structure of human IL-4 (2INT)

Available structures

PDB

Ortholog search: PDBe, RCSB

List of PDB id codes
1BBN, 1BCN, 1CYL, 1HIJ, 1HIK, 1HZI, 1IAR, 1ITI, 1ITL, 1ITM, 1RCB, 2B8U, 2B8X, 2B8Y, 2B8Z, 2B90, 2B91, 2CYK, 2D48, 2INT, 3BPL, 3BPN, 3QB7

Identifiers

Symbols

IL4; BCGF-1; BCGF1; BSF-1; BSF1; IL-4

External IDs

OMIM: 147780 MGI: 96556 HomoloGene: 491 GeneCards: IL4 Gene

Gene Ontology
Molecular function	â¢ cytokine activity â¢ interleukin-4 receptor binding â¢ protein binding â¢ growth factor activity
Cellular component	â¢ extracellular space â¢ external side of plasma membrane
Biological process	â¢ innate immune response in mucosa â¢ T-helper 1 cell lineage commitment â¢ negative regulation of acute inflammatory response â¢ negative regulation of chronic inflammatory response â¢ chemotaxis â¢ immune response â¢ cellular defense response â¢ female pregnancy â¢ response to nutrient â¢ cholesterol metabolic process â¢ regulation of proton transport â¢ response to organic cyclic compound â¢ B cell differentiation â¢ positive regulation of B cell proliferation â¢ B cell costimulation â¢ positive regulation of interleukin-10 production â¢ positive regulation of interleukin-13 production â¢ response to cytokine stimulus â¢ T-helper 2 cell cytokine production â¢ type 2 immune response â¢ positive regulation of T cell proliferation â¢ positive regulation of activated T cell proliferation â¢ regulation of phosphorylation â¢ response to drug â¢ positive regulation of tyrosine phosphorylation of Stat5 protein â¢ negative regulation of macrophage activation â¢ negative regulation of apoptotic process â¢ negative regulation of nitric oxide biosynthetic process â¢ T-helper 2 cell differentiation â¢ positive regulation of chemokine biosynthetic process â¢ connective tissue growth factor biosynthetic process â¢ regulation of isotype switching â¢ positive regulation of MHC class II biosynthetic process â¢ response to ethanol â¢ positive regulation of T cell differentiation â¢ negative regulation of osteoclast differentiation â¢ negative regulation of transcription, DNA-dependent â¢ positive regulation of transcription, DNA-dependent â¢ positive regulation of transcription from RNA polymerase II promoter â¢ positive regulation of isotype switching to IgE isotypes â¢ positive regulation of isotype switching to IgG isotypes â¢ regulation of immune response â¢ positive regulation of sequence-specific DNA binding transcription factor activity â¢ cellular response to mercury ion â¢ dendritic cell differentiation â¢ negative regulation of T-helper 17 cell differentiation
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 5:
132.01 â 132.02 Mb

Chr 11:
53.6 â 53.62 Mb

PubMed search

[1]

[2]

Interleukin 4

analysis of the solution structure of human interleukin 4 determined by heteronuclear three-dimensional nuclear magnetic resonance techniques

Identifiers

Symbol

IL4

Pfam clan

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

Interleukin 4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent studies suggest that basophils may be the effector cell.^[1] It is closely related and has functions similar to Interleukin 13.

Its receptor is the Interleukin-4 receptor.

[edit] Functions

It has many biological roles, including the stimulation of activated B-cell and T-cell proliferation, and the differentiation B cells into Plasma Cells.

It is a key regulator in humoral and adaptive immunity.

IL-4 induces B-cell class switching to IgE, and up-regulates MHC class II production. It also induces B cell class switching to IgG4.

IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell IL-12.

Overproduction of IL-4 is associated with allergies.^[2]

[edit] In inflammation and wound repair

Tissue macrophages play an important role in chronic inflammation and wound repair. The presence of IL-4 in extravascular tissues promotes alternative activation of macrophages into M2 cells and inhibits classical activation of macrophages into M1 cells. An increase in repair macrophages (M2) is coupled with secretion of IL-10 and TGF-Î² that result in a diminution of pathological inflammation. Release of arginase, proline, polyaminases and TGF-Î² by the activated M2 cell is tied with wound repair and fibrosis.^[3]

[edit] Clinical significance

IL-4 also has been shown to drive mitogenesis, dedifferentiation, and metastasis in rhabdomyosarcoma.^[4]

[edit] Structure

IL-4 has a compact, globular fold (similar to other cytokines), stabilised by 3 disulphide bonds.^[5] One half of the structure is dominated by a 4 alpha-helix bundle with a left-handed twist.^[6] The helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet.^[6]

[edit] History

This cytokine was co-discovered by Maureen Howard and William Paul^[7] and by Dr. Ellen Vitetta and her research group in 1982.

The nucleotide sequence for human IL-4 was isolated four years later confirming its similarity to a mouse protein called B-cell stimulatory factor-1 (BCSF-1).^[8]

[edit] See also

STAT6

[edit] References

^ Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. (2008). "A mechanism for the initiation of allergen-induced T helper type 2 responses". Nat Immunol 9 (3): 310â318. doi:10.1038/ni1558. PMID 18300366.
^ Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA (December 1997). "The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor". N. Engl. J. Med. 337 (24): 1720â5. doi:10.1056/NEJM199712113372403. PMID 9392697. Lay summary â eurekalert.org.
^ Jon Aster, Vinay Kumar, Abul K. Abbas; Nelson Fausto (2009). Robbins & Cotran Pathologic Basis of Disease (8th ed.). Philadelphia: Saunders. p. 54. ISBN 1-4160-3121-9.
^ Hosoyama T, Aslam MI, Abraham J, Prajapati SI, Nishijo K, Michalek JE, Zarzabal LA, Nelon LD, Guttridge DC, Rubin BP, Keller C (May 2011). "IL-4R Drives Dedifferentiation, Mitogenesis, and Metastasis in Rhabdomyosarcoma". Clin Cancer Res 17 (9): 2757â2766. doi:10.1158/1078-0432.CCR-10-3445. PMC 3087179. PMID 21536546. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3087179/.
^ Carr C, Aykent S, Kimack NM, Levine AD (February 1991). "Disulfide assignments in recombinant mouse and human interleukin 4". Biochemistry 30 (6): 1515â23. doi:10.1021/bi00220a011. PMID 1993171.
^ ^a ^b Walter MR, Cook WJ, Zhao BG, Cameron RP, Ealick SE, Walter RL, Reichert P, Nagabhushan TL, Trotta PP, Bugg CE (October 1992). "Crystal structure of recombinant human interleukin-4". J. Biol. Chem. 267 (28): 20371â6. PMID 1400355.
^ Howard M, Paul WE (1982). "Interleukins for B lymphocytes". Lymphokine Res. 1 (1): 1â4. PMID 6985399.
^ Yokota T et al. (1986). "Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities". Proc. Natl. Acad. Sci. U.S.A. 83 (16): 5894â8. doi:10.1073/pnas.83.16.5894. PMC 386403. PMID 3016727. //www.ncbi.nlm.nih.gov/pmc/articles/PMC386403/.

[edit] Further reading

Apte SH, Baz A, Kelso A, Kienzle N (2008). "Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells". Proc Natl Acad Sci U S A. 105 (45): 17475â80. doi:10.1073/pnas.0809549105. PMC 2580749. PMID 18988742. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2580749/.
Kay AB, Barata L, Meng Q, et al. (1997). "Eosinophils and eosinophil-associated cytokines in allergic inflammation". Int. Arch. Allergy Immunol. 113 (1â3): 196â9. doi:10.1159/000237545. PMID 9130521.
Marone G, Florio G, Petraroli A, de Paulis A (2001). "Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection". J. Allergy Clin. Immunol. 107 (1): 22â30. doi:10.1067/mai.2001.111589. PMID 11149986.
Marone G, Florio G, Triggiani M, et al. (2001). "Mechanisms of IgE elevation in HIV-1 infection". Crit. Rev. Immunol. 20 (6): 477â96. PMID 11396683.
Maeda S, Yanagihara Y (2001). "[Inflammatory cytokines (IL-4, IL-5 and IL-13)]". Nippon Rinsho 59 (10): 1894â9. PMID 11676128.
Izuhara K, Arima K, Yasunaga S (2003). "IL-4 and IL-13: their pathological roles in allergic diseases and their potential in developing new therapies". Current drug targets. Inflammation and allergy 1 (3): 263â9. doi:10.2174/1568010023344661. PMID 14561191.
Copeland KF (2006). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini reviews in medicinal chemistry 5 (12): 1093â101. doi:10.2174/138955705774933383. PMID 16375755.
Olver S, Apte S, Baz A, Kienzle N (2007). "The duplicitous effects of interleukin 4 on tumour immunity: how can the same cytokine improve or impair control of tumour growth?". Tissue Antigens 69 (4): 293â8. doi:10.1111/j.1399-0039.2007.00831.x. PMID 17389011.
Sokol CL, Chu NQ, Shuang Yu, Simone Nish, Terri Laufer & Ruslan Medzhitov (2009). "Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response". Nature Immunology 10 (7): 713â720. doi:10.1038/ni.1738. PMC 3252751. PMID 19465907. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3252751/.
Sokol CL, Chu NQ, Yu S, Nish SA, Laufer TM, Medzhitov R (July 2009). "Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response". Nat. Immunol. 10 (7): 713â20. doi:10.1038/ni.1738. PMC 3252751. PMID 19465907. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3252751/.

[edit] External links

Interleukin-4 at the US National Library of Medicine Medical Subject Headings (MeSH)
Interleukin-4 from Gentaur at Gentaur
Recombinant Human Interleukin-4 from Cornell University
Interleukin-4 from Allergy Glossary at Health On the Net Foundation

PDB gallery

1bbn: THREE-DIMENSIONAL SOLUTION STRUCTURE OF HUMAN INTERLEUKIN-4 BY MULTI-DIMENSIONAL HETERONUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

1bcn: THREE-DIMENSIONAL SOLUTION STRUCTURE OF HUMAN INTERLEUKIN-4 BY MULTI-DIMENSIONAL HETERONUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

1cyl: ASPECTS OF RECEPTOR BINDING AND SIGNALLING OF INTERLEUKIN-4 INVESTIGATED BY SITE-DIRECTED MUTAGENESIS AND NMR SPECTROSCOPY

1hij: INTERLEUKIN-4 MUTANT WITH ARG 88 REPLACED WITH GLN (R88Q)

1hik: INTERLEUKIN-4 (WILD-TYPE)

1hzi: INTERLEUKIN-4 MUTANT E9A

1iar: INTERLEUKIN-4 / RECEPTOR ALPHA CHAIN COMPLEX

1iti: THE HIGH RESOLUTION THREE-DIMENSIONAL SOLUTION STRUCTURE OF HUMAN INTERLEUKIN-4 DETERMINED BY MULTI-DIMENSIONAL HETERONUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

1itl: HUMAN INTERLEUKIN 4: THE SOLUTION STRUCTURE OF A FOUR-HELIX-BUNDLE PROTEIN

1itm: ANALYSIS OF THE SOLUTION STRUCTURE OF HUMAN INTERLEUKIN 4 DETERMINED BY HETERONUCLEAR THREE-DIMENSIONAL NUCLEAR MAGNETIC RESONANCE TECHNIQUES

1rcb: CRYSTAL STRUCTURE OF HUMAN RECOMBINANT INTERLEUKIN-4 AT 2.25 ANGSTROMS RESOLUTION

2b8u: Crystal structure of wildtype human Interleukin-4

2b8x: Crystal stucture of the interleukin-4 variant F82D

2b8y: Crystal structure of the interleukin-4 variant T13DF82D

2b8z: Crystal structure of the interleukin-4 variant R85A

2b90: Crystal structure of the interleukin-4 variant T13DR85A

2b91: Crystal structure of the interleukin-4 variant F82DR85A

2cyk: ASPECTS OF RECEPTOR BINDING AND SIGNALLING OF INTERLEUKIN-4 INVESTIGATED BY SITE-DIRECTED MUTAGENESIS AND NMR SPECTROSCOPY

2d48: Crystal structure of the Interleukin-4 variant T13D

2int: CRYSTAL STRUCTURE OF RECOMBINANT HUMAN INTERLEUKIN-4

Cell signaling: cytokines

By family

Chemokine

CCL	CCL1 CCL2/MCP-1 CCL3/MIP-1Î± CCL4/MIP-1Î² CCL5/RANTES CCL6 CCL7 CCL8 CCL9 CCL11 CCL12 CCL13 CCL14 CCL15 CCL16 CCL17 CCL18 CCL19 CCL20 CCL21 CCL22 CCL23 CCL24 CCL25 CCL26 CCL27 CCL28

CXCL	CXCL1/KC CXCL2 CXCL3 CXCL4 CXCL5 CXCL6 CXCL7 CXCL8/IL8 CXCL9 CXCL10 CXCL11 CXCL12 CXCL13 CXCL14 CXCL15 CXCL16 CXCL17

CX3CL	CX3CL1

XCL	XCL1 XCL2

TNF

Interleukin

Type I
(grouped by
receptor
subunit)

Î³-chain	IL2/IL15 IL4/IL13 IL7 IL9 IL21

Î²-chain	IL3 IL5 GM-CSF

IL6 like/gp130	IL6 IL11 IL27 IL30 IL31 +non IL OSM LIF CNTF CTF1

IL-12 family/IL12RB1	IL12 IL23 IL27 IL35

Other	IL14 IL16 IL32 IL34

Type II

IL-10 family

IL10/IL22
IL19
IL20
IL24
IL26
Interferon type III
- IL28/IFNL2+3
- IL29/IFNL1

Interferon

I	IFNA1 IFNA2 IFNA4 IFNA5 IFNA6 IFNA7 IFNA8 IFNA10 IFNA13 IFNA14 IFNA16 IFNA17 IFNA21 IFNB1 IFNK IFNW1

II	IFNG

Ig superfamily

IL-17 family

IL17/IL25 (IL17A)

Other

By function/
cell

proinflammatory cytokine
- IL1
- TNFA

Monokine
Lymphokine
- T_h1
  - IFNG
  - TNFB
- T_h2
  - IL4
  - IL5
  - IL6
  - IL10
  - IL13

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

This immunology article is a stub. You can help Wikipedia by expanding it.

This article incorporates text from the public domain Pfam and InterPro IPR002354

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Interleukin 4 Provide feedback

No Pfam abstract.

External database links

PANDIT:	PF00727
PROSITE:	PDOC00655
Pseudofam:	PF00727
SCOP:	2int
SYSTERS:	IL4

This tab holds annotation information from the InterPro database.

InterPro entry IPR002354

Cytokines are protein messengers that carry information from cell to cell [PUBMED:8151703]. Interleukin is one such molecule, and participates in several B-cell activation processes: e.g., it enhances production and secretion of IgG1 and IgE [PUBMED:3083412]; it induces expression of class II major histocompatability complex (MHC) molecules on resting B-cells; and it regulates expression of the low affinity Fc receptor for IgE on lymphocytes and monocytes. Interleukin-4 (IL4) has a compact, globular fold (similar to other cytokines), stabilised by 3 disulphide bonds [PUBMED:1993171]. One half of the structure is dominated by a 4 alpha-helix bundle with a left-handed twist [PUBMED:1400355]. The helices are anti-parallel, with 2 overhand connections, which fall into a 2-stranded anti-parallel beta-sheet [PUBMED:1400355].

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)
Molecular function	growth factor activity (GO:0008083)
Molecular function	interleukin-4 receptor binding (GO:0005136)
Biological process	immune response (GO:0006955)

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 4H_Cytokine (CL0053), which contains the following 22 members:

CNTF EPO_TPO Flt3_lig GM_CSF Hormone_1 IFN-gamma IL10 IL11 IL12 IL13 IL2 IL22 IL3 IL34 IL4 IL5 IL6 Interferon Leptin LIF_OSM PRF SCF

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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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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	Seed (8)	Full (198)	Representative proteomes				NCBI (186)	Meta (0)
	Seed (8)	Full (198)	RP15 (1)	RP35 (2)	RP55 (3)	RP75 (28)	NCBI (186)	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 (8)	Full (198)	Representative proteomes				NCBI (186)	Meta (0)
	Seed (8)	Full (198)	RP15 (1)	RP35 (2)	RP55 (3)	RP75 (28)	NCBI (186)	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 (8)	Full (198)	Representative proteomes				NCBI (186)	Meta (0)
	Seed (8)	Full (198)	RP15 (1)	RP35 (2)	RP55 (3)	RP75 (28)	NCBI (186)	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:

Pfam-B_833 (release 2.1)

Previous IDs:

none

Type:

Domain

Author:

Bateman A

Number in seed:

8

Number in full:

198

Average length of the domain:

84.40 aa

Average identity of full alignment:

48 %

Average coverage of the sequence by the domain:

78.13 %

HMM information

HMM build commands:

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

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

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.5	20.5
Trusted cut-off	20.7	20.5
Noise cut-off	19.5	20.4

Model length:

117

Family (HMM) version:

13

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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kingdom
phylum
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order
family
genus
species

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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.

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

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.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

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 IL4 domain has been found. There are 24 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: IL4 (PF00727)

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