Summary: Transforming growth factor beta like domain

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Wikipedia: Transforming growth factor beta superfamily
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Transforming growth factor beta superfamily Edit Wikipedia article

Transforming growth factor beta like domain

Structure of human transforming growth factor-beta 2.^[1]

Identifiers

Symbol

TGF_beta

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

The transforming growth factor beta (TGF-β) superfamily is a large family of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983.^[2]

Many proteins have since been described as members of the TGF-β superfamily in a variety of species, including invertebrates as well as vertebrates and categorized into 23 distinct gene types that fall into four major subfamilies:^[3]^[4]^[5]

the decapentaplegic-Vg-related (DVR) related subfamily (including the bone morphogenetic proteins and the growth differentiation factors)
the activin/inhibin subfamily
the TGF-β subfamily
a group encompassing various divergent members

Transforming growth factor-beta (TGF-beta)^[6] is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein. These proteins interact with a conserved family of cell surface serine/threonine-specific protein kinase receptors, and generate intracellular signals using a conserved family of proteins called SMADs. They play fundamental roles in the regulation of basic biological processes such as growth, development, tissue homeostasis and regulation of the immune system.^[3]

[edit] Structure

Proteins from the TGF-beta family are only active as homo- or heterodimer; the two chains being linked by a single disulfide bond. From X-ray studies of TGF-beta-2,^[7] it is known that all the other cysteines are involved in intrachain disulfide bonds. As shown in the following schematic representation, there are four disulfide bonds in the TGF-beta's and in inhibin beta chains, while the other members of this family lack the first bond.

                                                     interchain
                                                     |
          +------------------------------------------|+
          |                                          ||
xxxxcxxxxxCcxxxxxxxxxxxxxxxxxxCxxCxxxxxxxxxxxxxxxxxxxCCxxxxxxxxxxxxxxxxxxxCxCx
    |      |                  |  |                                        | |
    +------+                  +--|----------------------------------------+ |
                                 +------------------------------------------+

where 'C' denotes a conserved cysteine involved in a disulfide bond.

[edit] Examples

Human genes encoding proteins that contain this domain include:

AMH; ARTN; BMP10; BMP15; BMP2; BMP3; BMP4; BMP5; BMP6; BMP7; BMP8A; BMP8B; GDF1; GDF10; GDF11; GDF15; GDF2; GDF3; GDF3A; GDF5; GDF6; GDF7; GDF8; GDF9; GDNF; INHA; INHBA; INHBB; INHBC; INHBE; LEFTY1; LEFTY2; MSTN; NODAL; NRTN; PSPN; TGFB1; TGFB2; TGFB3;

[edit] References

^ Schlunegger MP, Grütter MG (July 1992). "An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-beta 2". Nature 358 (6385): 430–4. doi:10.1038/358430a0. PMID 1641027.
^ Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (June 1983). "Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization". J. Biol. Chem. 258 (11): 7155–60. PMID 6602130.
^ ^a ^b Herpin A, Lelong C, Favrel P (May 2004). "Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans". Dev. Comp. Immunol. 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644.
^ Burt DW (April 1992). "Evolutionary grouping of the transforming growth factor-beta superfamily". Biochem. Biophys. Res. Commun. 184 (2): 590–5. doi:10.1016/0006-291X(92)90630-4. PMID 1575734.
^ Burt DW, Law AS (1994). "Evolution of the transforming growth factor-beta superfamily". Prog. Growth Factor Res. 5 (1): 99–118. doi:10.1016/0955-2235(94)90020-5. PMID 8199356.
^ Roberts AB, Sporn MB (1990). Peptide growth factors and their receptors. Berlin: Springer-Verlag. ISBN 3-540-51184-9.
^ Daopin S, Piez KA, Ogawa Y, Davies DR (July 1992). "Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily". Science 257 (5068): 369–73. doi:10.1126/science.1631557. PMID 1631557.

v t e Intercellular signaling peptides and proteins / ligands

Growth factors	Endothelial growth factor Epidermal growth factor Fibroblast growth factor Nerve growth factor Platelet-derived growth factor Transforming growth factor beta superfamily

Ephrin	EFNA1 EFNA2 EFNA3 EFNA4 EFNA5 EFNB1 EFNB2 EFNB3

Other	Adipokine Agouti signaling protein Agouti-related protein Angiogenic protein CCN intercellular signaling protein Cysteine-rich protein 61 Connective tissue growth factor Nephroblastoma overexpressed protein Cytokine Endothelin EDN1 EDN2 EDN3 Hedgehog protein Interferon Kinin Parathyroid hormone-related protein Semaphorin Somatomedin Tolloid-like metalloproteinase Tumor necrosis factor Wnt protein

see also extracellular ligand disorders 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)

v t e Cell signaling: TGF beta signaling pathway

TGF beta superfamily of ligands	TGF beta family (TGF-β1, TGF-β2, TGF-β3) Bone morphogenetic proteins (BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10 , BMP15) Growth differentiation factors (GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, Myostatin/GDF8, GDF9, GDF10, GDF11, GDF15) Other (Activin and inhibin, Anti-müllerian hormone, Nodal)

TGF beta receptors (Activin, BMP)	TGFBR1: Activin type 1 receptors (ACVR1, ACVR1B, ACVR1C) · ACVRL1 · BMPR1 (BMPR1A · BMPR1B) TGFBR2: Activin type 2 receptors (ACVR2A, ACVR2B) · AMHR2 · BMPR2 TGFBR3: betaglycan

Transducers/SMAD	R-SMAD (SMAD1, SMAD2, SMAD3, SMAD5, SMAD9) · I-SMAD (SMAD6, SMAD7) · SMAD4

Ligand inhibitors	Cerberus · Chordin · DAN · Decorin · Follistatin · Gremlin · Lefty · LTBP1 · Noggin · THBS1

Coreceptors	BAMBI · Cripto

Other	SARA

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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Literature references

Daopin S, Piez KA, Ogawa Y, Davies DR; , Science 1992;257:369-373.: Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily. PUBMED:1631557 EPMC:1631557
Griffith DL, Keck PC, Sampath TK, Rueger DC, Carlson WD; , Proc Natl Acad Sci U S A 1996;93:878-883.: Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor beta superfamily. PUBMED:8570652 EPMC:8570652
Eigenbrot C, Gerber N; , Nat Struct Biol 1997;4:435-438.: X-ray structure of glial cell-derived neurotrophic factor at 1.9 A resolution and implications for receptor binding. PUBMED:9187648 EPMC:9187648

External database links

HOMSTRAD:	tgfb
PANDIT:	PF00019
PROSITE:	PDOC00223
Pseudofam:	PF00019
SCOP:	1tfg
SYSTERS:	TGF_beta

This tab holds annotation information from the InterPro database.

InterPro entry IPR001839

Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein [PUBMED:8679613].

A number of proteins are known to be related to TGF-beta-1 [PUBMED:1575734, PUBMED:8199356]. Proteins from the TGF-beta family are only active as homo- or heterodimer; the two chains being linked by a single disulphide bond. From X-ray studies of TGF-beta-2 [PUBMED:1631557], it is known that all the other cysteines are involved in intrachain disulphide bonds. There are four disulphide bonds in the TGF-beta's and in inhibin beta chains, while the other members of this family lack the first bond.

The regulatory cytokine TGFbeta exerts tumour-suppressive effects, but also modulates cell invasion and immune regulation [PUBMED:18662538]. Misregulation of the TGF-beta signalling pathway can result in tumour development.

Gene Ontology

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

Molecular function

growth factor activity (GO:0008083)

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 Cystine-knot (CL0079), which contains the following 9 members:

Coagulin Cys_knot DAN Hormone_6 NGF Noggin PDGF Sclerostin TGF_beta

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 (20)	Full (3712)	Representative proteomes				NCBI (3220)	Meta (0)
	Seed (20)	Full (3712)	RP15 (194)	RP35 (298)	RP55 (677)	RP75 (1288)	NCBI (3220)	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 (20)	Full (3712)	Representative proteomes				NCBI (3220)	Meta (0)
	Seed (20)	Full (3712)	RP15 (194)	RP35 (298)	RP55 (677)	RP75 (1288)	NCBI (3220)	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 (20)	Full (3712)	Representative proteomes				NCBI (3220)	Meta (0)
	Seed (20)	Full (3712)	RP15 (194)	RP35 (298)	RP55 (677)	RP75 (1288)	NCBI (3220)	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:

Prosite

Previous IDs:

TGF-beta;

Type:

Domain

Author:

Sonnhammer ELL, Griffiths-Jones SR

Number in seed:

20

Number in full:

3712

Average length of the domain:

95.50 aa

Average identity of full alignment:

38 %

Average coverage of the sequence by the domain:

29.32 %

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	20.3	20.3
Trusted cut-off	20.6	20.4
Noise cut-off	19.7	20.1

Model length:

105

Family (HMM) version:

15

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
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.

Interactions

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

TGF_beta Activin_recp PRKCSH Kazal_1

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 TGF_beta domain has been found. There are 111 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: TGF_beta (PF00019)

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