Summary: Interleukin-4 receptor alpha chain, N-terminal

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Wikipedia: Interleukin-4 receptor
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Interleukin-4 receptor Edit Wikipedia article

Interleukin 4 receptor

PDB rendering based on 1iar.

Available structures

PDB

Ortholog search: PDBe, RCSB

List of PDB id codes
1IAR, 1IRS, 3BPL, 3BPN, 3BPO

Identifiers

Symbols

IL4R; CD124; IL-4RA; IL4RA

External IDs

OMIM: 147781 MGI: 105367 HomoloGene: 7784 GeneCards: IL4R Gene

Gene Ontology
Molecular function	• interleukin-4 receptor activity • receptor signaling protein activity • protein binding • insulin receptor substrate binding
Cellular component	• extracellular space • integral to plasma membrane
Biological process	• production of molecular mediator involved in inflammatory response • immune response • signal transduction • ovulation • interleukin-4-mediated signaling pathway • regulation of cell proliferation • positive regulation of macrophage activation • response to estrogen stimulus • negative regulation of T-helper 1 cell differentiation • positive regulation of T-helper 2 cell differentiation • positive regulation of chemokine secretion
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 16:
27.32 – 27.38 Mb

Chr 7:
125.55 – 125.58 Mb

PubMed search

[1]

[2]

Interleukin-4 receptor alpha chain, N-terminal

interleukin-4 / receptor alpha chain complex

Identifiers

Symbol

IL4Ra_N

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

Interleukin 4 receptor is a type I cytokine receptor. IL4R is its human gene.

[edit] Function

This gene encodes the alpha chain of the interleukin-4 receptor, a type I transmembrane protein that can bind interleukin 4 and interleukin 13 to regulate IgE antibody production in B cells. Among T cells, the encoded protein also can bind interleukin 4 to promote differentiation of Th2 cells. A soluble form of the encoded protein can be produced by an alternate splice variant or by proteolysis of the membrane-bound protein, and this soluble form can inhibit IL4-mediated cell proliferation and IL5 upregulation by T-cells. Allelic variations in this gene have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitis, asthma, or eczema. Two transcript variants encoding different isoforms, a membrane-bound and a soluble form, have been found for this gene.^[1]

The binding of IL-4 or IL-13 to the IL-4 receptor on the surface of macrophages results in the alternative activation of those macrophages. Alternatively activated macrophages (AAMΦ) downregulate inflammatory mediators such as IFNγ during immune responses, particularly with regards to helminth infections.^[2]

[edit] Interactions

Interleukin-4 receptor has been shown to interact with SHC1.^[3]^[4]

[edit] Structure

The N-terminal (extracellular) portion of interleukin-4 is related in overall topology to fibronectin type III modules and folds into a sandwich comprising seven antiparallel beta sheets arranged in a three-strand and a four-strand beta-pleated sheet. They are required for binding of interleukin-4 to the receptor alpha chain, which is a crucial event for the generation of a Th2-dominated early immune response.^[5]

[edit] See also

Cluster of differentiation

[edit] References

^ "Entrez Gene: IL4R interleukin 4 receptor". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3566.
^ Tundup S, Srivastava L, Harn DA (April 2012). "Polarization of host immune responses by helminth-expressed glycans". Ann. N. Y. Acad. Sci. 1253: E1–E13. doi:10.1111/j.1749-6632.2012.06618.x. PMID 22974465.
^ Ikizawa K, Yanagihara Y (February 2000). "Possible involvement of Shc in IL-4-induced germline epsilon transcription in a human B cell line". Biochem. Biophys. Res. Commun. 268 (1): 54–9. doi:10.1006/bbrc.2000.2080. PMID 10652211.
^ Kashiwada M, Giallourakis CC, Pan PY, Rothman PB (December 2001). "Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor associates with SH2-containing phosphatases and regulates IL-4-induced proliferation". J. Immunol. 167 (11): 6382–7. PMID 11714803.
^ Hage T, Sebald W, Reinemer P (April 1999). "Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface". Cell 97 (2): 271–81. doi:10.1016/S0092-8674(00)80736-9. PMID 10219247.

[edit] Further reading

Nelms K, Keegan AD, Zamorano J, et al. (1999). "The IL-4 receptor: signaling mechanisms and biologic functions.". Annu. Rev. Immunol. 17 (1): 701–38. doi:10.1146/annurev.immunol.17.1.701. PMID 10358772.
Jiang H, Harris MB, Rothman P (2000). "IL-4/IL-13 signaling beyond JAK/STAT.". J. Allergy Clin. Immunol. 105 (6 Pt 1): 1063–70. doi:10.1067/mai.2000.107604. PMID 10856136.

[edit] External links

CD124 Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery

1iar: INTERLEUKIN-4 / RECEPTOR ALPHA CHAIN COMPLEX

v t e Proteins: clusters of differentiation (see also list of human clusters of differentiation)

1-50	CD1 a-c 1A 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50

51-100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100

101-150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150

151-200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200

201-250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249

251-300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299

301-350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350

Cytokine receptors

Chemokine receptor
(GPCRs)

CC	CCR1/CCRL1 CCR2 CCRL2 CCR3 CCR4 CCR5 CCR6 CCR7 CCR8 CCR9 CCR10

CXC	IL-8 CXCR1 CXCR2 CXCR3 CXCR4 CXCR5 CXCR6 CXCR7

Other	CX3C CX3CR1 XC XCR1 CCBP2 CMKLR1

TNF receptor

1-10	TNFRSF1 (CD120) TNFRSF1A (CD120a) TNFRSF1B (CD120b) TNFRSF3 (Lymphotoxin beta receptor) TNFRSF4 (CD134) TNFRSF5 (CD40) TNFRSF6 (FAS) TNFRSF6B TNFRSF7 (CD27) TNFRSF8 (CD30) TNFRSF9 (CD137)

11-20	TNFRSF10A (CD261) TNFRSF10B (CD262) TNFRSF10C (CD263) TNFRSF10D (CD264) TNFRSF11A (CD265/RANK) TNFRSF11B (Osteoprotegerin) TNFRSF12A (CD266) TNFRSF13B (CD267) TNFRSF13C TNFRSF14 (CD268) TNFRSF16 (Nerve growth factor receptor) TNFRSF17 (CD269) TNFRSF18 TNFRSF19

21-25	TNFRSF21 TNFRSF25 TNFRSF27

JAK-STAT

Type I

γ-chain	Interleukin receptors IL2R/IL2RA/IL2RB/IL15R IL4R/IL13R/IL13RA1/IL13RA2 IL7R/IL7RA IL9R IL21R

β-chain	Interleukin receptors IL3R/IL3RA IL5R/IL5RA GM-CSF

gp130	Interleukin receptors IL6RA 11/IL11RA 27/IL27RA OSMR LIFR CNTFR

IL12RB1	Interleukin receptors IL12R/IL12RB1/IL12RB2 IL23R23

Other	other CSF receptors EPO G-CSF Thrombopoietin hormone receptor: GH prolactin

Type II

Ig superfamily

IL-17 family

IL-17
- IL17RA
- IL17RB
- IL17RC
- IL17RD
- IL17RE

S/T

TGF-beta
- TGFBR1
- TGFBR2

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 article incorporates text from the public domain Pfam and InterPro IPR015319

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Interleukin-4 receptor alpha chain, N-terminal Provide feedback

Members of this family are related in overall topology to fibronectin type III modules and fold into a sandwich comprising seven antiparallel beta sheets arranged in a three-strand and a four-strand beta-pleated sheet. They are required for binding of interleukin-4 to the receptor alpha chain, which is a crucial event for the generation of a Th2-dominated early immune response [1].

Literature references

Hage T, Sebald W, Reinemer P; , Cell. 1999;97:271-281.: Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface. PUBMED:10219247 EPMC:10219247

External database links

PANDIT:	PF09238
Pseudofam:	PF09238
SCOP:	1iar
SYSTERS:	IL4Ra_N

This tab holds annotation information from the InterPro database.

InterPro entry IPR015319

Members of this family are related in overall topology to fibronectin type III modules and fold into a sandwich comprising seven antiparallel beta sheets arranged in a three-strand and a four-strand beta-pleated sheet. They are required for binding of interleukin-4 to the receptor alpha chain, which is a crucial event for the generation of a Th2-dominated early immune response [PUBMED:10219247].

Gene Ontology

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

Cellular component	integral to membrane (GO:0016021)
Molecular function	cytokine receptor activity (GO:0004896)
Biological process	production of molecular mediator involved in inflammatory response (GO:0002532)

Domain organisation

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

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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:

seed: the curated alignment from which the HMM for the family is built
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

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
FASTA
MSF

You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

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 (7)	Full (71)	Representative proteomes				NCBI (64)	Meta (0)
	Seed (7)	Full (71)	RP15 (1)	RP35 (6)	RP55 (10)	RP75 (27)	NCBI (64)	Meta (0)
Jalview	View	View	View	View	View	View	View
HTML	View	View	View	View	View	View
PP/heatmap	₁	View	View	View	View	View
Pfam viewer	View	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (7)	Full (71)	Representative proteomes				NCBI (64)	Meta (0)
	Seed (7)	Full (71)	RP15 (1)	RP35 (6)	RP55 (10)	RP75 (27)	NCBI (64)	Meta (0)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

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 (7)	Full (71)	Representative proteomes				NCBI (64)	Meta (0)
	Seed (7)	Full (71)	RP15 (1)	RP35 (6)	RP55 (10)	RP75 (27)	NCBI (64)	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.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

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.

Note: You can also download the data file for the tree.

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:

pdb_1iar

Previous IDs:

none

Type:

Domain

Author:

Sammut SJ

Number in seed:

7

Number in full:

71

Average length of the domain:

90.20 aa

Average identity of full alignment:

45 %

Average coverage of the sequence by the domain:

18.27 %

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	22.9	22.9
Trusted cut-off	23.7	26.1
Noise cut-off	22.5	22.8

Model length:

95

Family (HMM) version:

5

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

Sunburst controls

Show

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

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.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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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
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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 IL4Ra_N domain has been found. There are 4 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.

Loading structure mapping...

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: IL4Ra_N (PF09238)

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