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172  structures 221  species 6  interactions 3887  sequences 94  architectures

Family: TNFR_c6 (PF00020)

Summary: TNFR/NGFR cysteine-rich region

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This is the Wikipedia entry entitled "Tumor necrosis factor receptor". More...

Tumor necrosis factor receptor Edit Wikipedia article

TNFR/NGFR cysteine-rich region
PDB 1tnr EBI.jpg
Structure of the soluble human 55 kd TNF receptor-human TNF beta complex.[1]
Symbol TNFR_c6
Pfam PF00020
InterPro IPR011614
SCOP 1tnr

The tumor necrosis factor receptor superfamily (TNFRSF) is a group of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain.[2][3] With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha.[4] In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrame. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms (e.g. TNFR1), and some lack a TMD entirely (e.g. DcR3). In addition, most TNF receptors require specific adaptor protein such as TRADD, TRAF, RIP and FADD for downstream signalling. TNF receptors are primarily involved in apoptosis and inflammation, but they can also take part in other signal transduction pathways, such as proliferation, survival, and differentiation. TNF receptors are expressed in a wide variety of tissues in mammals, especially in leukocytes.[4]

The term death receptor refers to those members of the TNF receptor superfamily that contain a death domain, such as TNFR1, Fas receptor, DR4 and DR5.[4] They were named after the fact that they seemed to play an important role in apoptosis (programmed cell death), although they are now known to play other roles as well.[5]

In the strict sense, the term TNF receptor is often used to refer to the archetypal members of the superfamily, namely TNFR1 and TNFR2, which recognize TNF-alpha.


There are 27 family members, numerically classified as TNFRSF#, where # denotes the member number, sometimes followed a letter.[2]

Type Protein (member #) Synonyms Gene Ligand(s)
1 Tumor necrosis factor receptor 1 (1A) CD120a TNFRSF1A TNF-alpha (cachectin)
Tumor necrosis factor receptor 2 (1B) CD120b TNFRSF1B
3 Lymphotoxin beta receptor (3) CD18 LTBR Lymphotoxin beta (TNF-C)
4 OX40 (4) CD134 TNFRSF4 OX40L
5 CD40 (5) Bp50 CD40 CD154
6 Fas receptor (6) Apo-1, CD95 FAS FasL
Decoy receptor 3 (6B) TR6, M68 TNFRSF6B FasL, LIGHT, TL1A
7 CD27 (7) S152, Tp55 CD27 CD70, Siva
8 CD30 (8) Ki-1 TNFRSF8 CD153
9 4-1BB (9) CD137 TNFRSF9 4-1BB ligand
10 Death receptor 4 (10A) TRAILR1, Apo-2, CD261 TNFRSF10A TRAIL
Death receptor 5 (10B) TRAILR2, CD262 TNFRSF10B
Decoy receptor 1 (10C) TRAILR3, LIT, TRID, CD263 TNFRSF10C
Decoy receptor 2 (10D) TRAILR4, TRUNDD, CD264 TNFRSF10D
Osteoprotegerin (11B) OCIF, TR1 TNFRSF11B
12 TWEAK receptor (12A) Fn14, CD266 TNFRSF12A TWEAK
BAFF receptor (13C) CD268 TNFRSF13C BAFF
14 Herpesvirus entry mediator (14) ATAR, TR2, CD270 TNFRSF14 LIGHT
16 Nerve growth factor receptor (16) p75NTR, CD271 NGFR NGF, BDNF, NT-3, NT-4
17 B-cell maturation antigen (17) TNFRSF13A, CD269 TNFRSF17 BAFF
18 Glucocorticoid-induced TNFR-related (18) AITR, CD357 TNFRSF18 GITR ligand
19 TROY (19) TAJ, TRADE TNFRSF19 unknown
21 Death receptor 6 (21) CD358 TNFRSF21
25 Death receptor 3 (25) Apo-3, TRAMP, LARD, WS-1 TNFRSF25 TL1A
27 Ectodysplasin A2 receptor (27) XEDAR EDA2R EDA-A2


  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ a b c Gravestein, LA; Borst, J (December 1998). "Tumor necrosis factor receptor family members in the immune system.". Seminars in immunology 10 (6): 423–34. PMID 9826575. 
  5. ^ Ashkenazi, A.; Dixit, VM (1998). "Death Receptors: Signaling and Modulation". Science 281 (5381): 1305–8. doi:10.1126/science.281.5381.1305. PMID 9721089. 

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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.

TNFR/NGFR cysteine-rich region Provide feedback

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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:

                  +-------------+    +--------------+
                  |             |    |              |
                                  |            |
'C': conserved cysteine involved in a disulphide bond.

Gene Ontology

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Domain organisation

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Curation and family details

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Seed source: Swissprot_feature_table
Previous IDs: none
Type: Domain
Author: Sonnhammer ELL
Number in seed: 639
Number in full: 3887
Average length of the domain: 39.50 aa
Average identity of full alignment: 28 %
Average coverage of the sequence by the domain: 16.75 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 20.6
Trusted cut-off 27.0 20.6
Noise cut-off 26.9 20.5
Model length: 39
Family (HMM) version: 14
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Species distribution

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Archea Archea Eukaryota Eukaryota
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Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 6 interactions for this family. More...



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 172 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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