Summary

TNF(Tumour Necrosis Factor) family

No Pfam abstract.

Literature references

Copley RR; , J Mol Med 1999;77:361-363.: The gene for X-linked anhidrotic ectodermal dysplasia encodes a TNF- like domain. PUBMED:10353440

InterPro entry IPR006052

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities PUBMED:8095800, PUBMED:1377364, PUBMED:. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia PUBMED:2989794, PUBMED:3349526. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine PUBMED:2268312. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers PUBMED:2777790. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide PUBMED:2777790.

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

The following cytokines can be grouped into a family on the basis of sequence, functional, and structural similarities PUBMED:8095800, PUBMED:1377364, PUBMED::

Tumor Necrosis Factor (TNF) (also known as cachectin or TNF-alpha) PUBMED:3061461, PUBMED:1850405 is a cytokine which has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; finally, it can stimulate cell proliferation and induce cell differentiation under certain conditions.
Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta), two related cytokines produced by lymphocytes and which are cytotoxic for a wide range of tumor cells in vitro and in vivo PUBMED:7916655.
T cell antigen gp39 (CD40L), a cytokine which seems to be important in B-cell development and activation.
CD27L, a cytokine which plays a role in T-cell activation. It induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells.
CD30L, a cytokine which induces proliferation of T cells.
FASL, a cytokine involved in cell death PUBMED:7505205.
4-1BBL, a inducible T cell surface molecule that contributes to T-cell stimulation.
OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production PUBMED:8076595.
TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis PUBMED:8777713.
TNF-alpha is synthesised as a type II membrane protein which then undergoes post-translational cleavage liberating the extracellular domain. CD27L, CD30L, CD40L, FASL, LT-beta, 4-1BBL and TRAIL also appear to be type II membrane proteins. LT-alpha is a secreted protein.

All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. The PROSITE pattern for this family is located in a beta-strand in the central section of the protein which is conserved across all members.

Clan

This family is a member of clan C1q_TNF (CL0100), which contains the following 2 members:

C1q TNF

Gene Ontology

Cellular component	membrane (GO:0016020)
Molecular function	tumor necrosis factor receptor binding (GO:0005164)
Biological process	immune response (GO:0006955)

External database links

HOMSTRAD:	TNF
PANDIT:	PF00229
PROSITE:	PDOC00224
SCOP:	1tnf
SYSTERS:	TNF

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

There are various ways to view or download the sequence alignments that we store. You can use a sequence viewer to look at either the seed or full alignment for the family, or you can look at a plain text version of the sequence in a variety of different formats. More...

View options

Alignment:	Seed (52) Full (520) NCBI (2603) Metagenomics (10)
Viewer:

Formatting options

Alignment:	Seed (52) Full (520)
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

Very large alignments can often cause problems for the formatting tool above. If you find that downloading or viewing a large alignment is problematic, you can also download a gzip-compressed, Stockholm-format file containing the seed or full alignment for this family.

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

The main seed and full alignments are generated using sequences from the UniProt sequence database. However, we also generate alignments using sequences from the NCBI sequence database and the "metaseq" metagenomics dataset.

You can view alignments from these two additional datasets using the form above, or you can download alignments of NCBI or metagenomics sequences, as gzip-compressed files.

Pfam alignments:	Seed (52) Full (520) NCBI (2603) Metagenomics (10)
Full length sequences	Full-sequences (520)

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 HMMER2.

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. 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 or full alignments.

Note: You can also download the data files for the seed, full, NCBI or metagenomics trees.

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:

none

Type:

Domain

Author:

Finn RD

Number in seed:

52

Number in full:

520

Average length of the domain:

119.70 aa

Average identity of full alignment:

27 %

Average coverage of the sequence by the domain:

49.47 %

HMM information

HMM build commands:

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

search method: hmmsearch -Z 9421015 -E 1000 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.9	20.9
Trusted cut-off	21.0	22.0
Noise cut-off	20.8	20.6

Model length:

127

Family (HMM) version:

11

Download:

download the raw HMM for this family

Species distribution

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
save a plain text representation of the tree

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Interactions

There are 5 interactions for this family. More...

BaffR-Tall_bind TNF TACI-CRD2 BCMA-Tall_bind TNFR_c6

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 TNF domain has been found.

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Family: TNF (PF00229)

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