Summary: TNFR/NGFR cysteine-rich region

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Wikipedia: Tumor necrosis factor receptor
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Tumor necrosis factor receptor Edit Wikipedia article

TNFR/NGFR cysteine-rich region

Structure of the soluble human 55 kd TNF receptor-human TNF beta complex.^[1]

Identifiers

Symbol

TNFR_c6

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

A tumor necrosis factor receptor (TNFR), or death receptor, is a trimeric^[2] cytokine receptor that binds tumor necrosis factors (TNF). The receptor cooperates with an adaptor protein (such as TRADD, TRAF, RIP), which is important in determining the outcome of the response (e.g. apoptosis, inflammation).

Because "TNF" is often used to describe TNF alpha, "TNFR" is often used to describe the receptors that bind to TNF alpha - namely, CD120. However, there are several other members of this family that bind to the other TNFs.^[3]^[4]

[edit] Members

Family members include:^[3]

Type	Protein	Aliases	Gene
1 (CD120)	CD120a		TNFRSF1A
1 (CD120)	CD120b		TNFRSF1B
3	Lymphotoxin β receptor	TNFRSF3	LTBR
4	CD134		TNFRSF4
5	CD40	TNFRSF5	CD40
6	FAS	TNFRSF6	FAS
6	TNFRSF6B		TNFRSF6B
7	CD27	TNFRSF7	CD27
8	CD30		TNFRSF8
9	CD137		TNFRSF9
10	TNFRSF10A	DR4	TNFRSF10A
	TNFRSF10B	DR5	TNFRSF10B
	TNFRSF10C		TNFRSF10C
	TNFRSF10D		TNFRSF10D
11	RANK		TNFRSF11A
11	Osteoprotegerin		TNFRSF11B
12	TNFRSF12A	Fn14	TNFRSF12A
13	TNFRSF13B		TNFRSF13B
13	TNFRSF13C		TNFRSF13C
14	TNFRSF14		TNFRSF14
16	Nerve growth factor receptor	TNFRSF16	NGFR
17	TNFRSF17		TNFRSF17
18	TNFRSF18		TNFRSF18
19	TNFRSF19		TNFRSF19
21	TNFRSF21	DR6	TNFRSF21
25	TNFRSF25		TNFRSF25
27	Ectodysplasin A2 receptor	TNFRSF27	EDA2R

[edit] References

^ Banner DW, D'Arcy A, Janes W et al. (May 1993). "Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation". Cell 73 (3): 431–45. doi:10.1016/0092-8674(93)90132-A. PMID 8387891.
^ Ashkenazi, A.; Dixit, VM (1998). "Death Receptors: Signaling and Modulation". Science 281 (5381): 1305–8. doi:10.1126/science.281.5381.1305. PMID 9721089.
^ ^a ^b Locksley RM, Killeen N, Lenardo MJ (2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407.
^ Hehlgans T, Pfeffer K (2005). "The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games". Immunology 115 (1): 1–20. doi:10.1111/j.1365-2567.2005.02143.x. PMC 1782125. PMID 15819693.

[edit] Further reading

Kavurma MM, Tan NY, Bennett MR. (2008). "Death receptors and their ligands in atherosclerosis". Arterioscler Thromb Vasc Biol. 28 (10): 1694–702. doi:10.1161/ATVBAHA.107.155143. PMID 18669890.
Hatano, E. (2007). "Tumor necrosis factor signaling in hepatocyte apoptosis". J Gastroenterol Hepatol. 22: S43–44. doi:10.1111/j.1440-1746.2006.04645.x. PMID 17567463.

[edit] External links

Tumor Necrosis Factor Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

Membrane proteins, receptors: cell surface receptors

G protein-coupled receptor

Class A	Eicosanoid receptor (Prostaglandin receptor) Protease-activated receptor Neurotransmitter receptor Purinergic receptor Biogenic amine receptor Olfactory receptor

Class B	Secretin receptor

Class C	Metabotropic glutamate receptor

Class D	Pheromone receptor

Class E	cAMP receptor

Class F	Frizzled/smoothened

Ligand-gated ion channel

Purinergic receptor

Enzyme-linked receptor

Other/ungrouped

See also: cell surface receptor deficiencies
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)

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)

Apoptosis signaling pathway

Fas path

Ligand	Fas ligand

Receptor	Fas receptor

Intracellular	Death-inducing signaling complex DAXX ASK1 FADD Caspase 8 BID Cytochrome c Caspase 9 Caspase 3 Pro-apoptotic: BAX BAK1/Bcl-2 homologous antagonist killer Bcl-2-associated death promoter Anti-apoptotic: Bcl-2 Bcl-xL

TNF path

Ligand	Tumor necrosis factors

Receptor	Tumor necrosis factor receptor

Intracellular	TRADD FADD Caspase 8 Caspase 3 BID TRAF2 ASK-1 MEKK1 IKK IκBα MKK7 JNK NF-κB

Other

Intracellular	IAPs XIAP NAIP Survivin c-IAP-1 c-IAP-2 Apoptosis-inducing factor

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)

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TNFR/NGFR cysteine-rich region Provide feedback

No Pfam abstract.

Internal database links

SCOOP:

NCD3G GCC2_GCC3

External database links

HOMSTRAD:	TNFR_c6
PANDIT:	PF00020
PROSITE:	PDOC00561
Pseudofam:	PF00020
SCOP:	1tnr
SYSTERS:	TNFR_c6

This tab holds annotation information from the InterPro database.

InterPro entry IPR001368

A number of proteins, some of which are known to be receptors for growth factors, have been found to contain a cysteine-rich domain of about 110 to 160 amino acids in their N-terminal part, that can be subdivided into four (or in some cases, three) modules of about 40 residues containing 6 conserved cysteines. Some of the proteins containing this domain are listed below [PUBMED:2174582, PUBMED:15335933, PUBMED:15335677]:

Tumor Necrosis Factor type I and type II receptors (TNFR). Both receptors bind TNF-alpha and TNF-beta, but are only similar in the cysteine-rich region
Shope fibroma virus soluble TNF receptor (protein T2)
Lymphotoxin alpha/beta receptor
Low-affinity nerve growth factor receptor (LA-NGFR) (p75)
CD40 (Bp50), the receptor for the CD40L (or TRAP) cytokine
CD27, the receptor for the CD27L cytokine
CD30, the receptor for the CD30L cytokine
T-cell protein 4-1BB, the receptor for the 4-1BBL putative cytokine
FAS antigen (or APO-1), the receptor for FASL, a protein involved in apoptosis (programmed cell death)
T-cell antigen OX40, the receptor for the OX40L cytokine
Wsl-1, a receptor (for a yet undefined ligand) that mediates apoptosis
Vaccinia virus protein A53 (SalF19R)

It has been shown [PUBMED:8387891] that the six cysteines all involved in intrachain disulphide bonds. A schematic representation of the structure of the 40 residue module of these receptors is shown below:

                  +-------------+    +--------------+
                  |             |    |              |
                 xCxxxxxxxxxxxxxCxCxxCxxxxxxxxxCxxxxCxx
                                  |            |
                                  +------------+

'C': conserved cysteine involved in a disulphide bond.

Gene Ontology

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

Molecular function

protein binding (GO:0005515)

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 (37)	Full (2327)	Representative proteomes				NCBI (2043)	Meta (25)
	Seed (37)	Full (2327)	RP15 (184)	RP35 (248)	RP55 (442)	RP75 (889)	NCBI (2043)	Meta (25)
Jalview	View	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 (37)	Full (2327)	Representative proteomes				NCBI (2043)	Meta (25)
	Seed (37)	Full (2327)	RP15 (184)	RP35 (248)	RP55 (442)	RP75 (889)	NCBI (2043)	Meta (25)
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 (37)	Full (2327)	Representative proteomes				NCBI (2043)	Meta (25)
	Seed (37)	Full (2327)	RP15 (184)	RP35 (248)	RP55 (442)	RP75 (889)	NCBI (2043)	Meta (25)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	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:

Swissprot_feature_table

Previous IDs:

none

Type:

Domain

Author:

Sonnhammer ELL

Number in seed:

37

Number in full:

2327

Average length of the domain:

38.90 aa

Average identity of full alignment:

30 %

Average coverage of the sequence by the domain:

15.97 %

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	20.6	20.6
Trusted cut-off	20.6	20.6
Noise cut-off	20.5	20.5

Model length:

39

Family (HMM) version:

13

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
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
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Interactions

There are 4 interactions for this family. More...

TNF TNFR_c6 NGF V-set

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 TNFR_c6 domain has been found. There are 88 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: TNFR_c6 (PF00020)

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