Summary: 7 transmembrane receptor (Secretin family)

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Wikipedia: Secretin receptor family
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Secretin receptor family Edit Wikipedia article

Secretin family of 7 transmembrane receptors

Structure of a 31 amino acid fragment of the extracellular N-terminus of the human parathyroid hormone receptor.^[1]

Identifiers

Symbol

7tm_2

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

Secretin family of 7 transmembrane receptors is a family of evolutionarily related proteins.^[2]

This family is known as Family B, the secretin-receptor family or family 2 of the G-protein-coupled receptors (GPCR). Many secretin receptors are regulated by peptide hormones from the glucagon hormone family.

The secretin-receptor family GPCRs include vasoactive intestinal peptide receptors and receptors for secretin, calcitonin and parathyroid hormone/parathyroid hormone-related peptides. These receptors activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. The receptors in this family have 7 transmembrane helices, like rhodopsin-like GPCRs. However, there is no significant sequence identity between these two GPCR families and the secretin-receptor family has its own characteristic 7TM signature.

The secretin-receptor family GPCRs exist in many animal species, but have not been found in plants, fungi or prokaryotes. Three distinct sub-families (B1-B3) are recognized.

[edit] Subfamily B1

Subfamily B1 contains classical hormone receptors, such as receptors for secretin and glucagon, that are all involved in cAMP-mediated signalling pathways.

Pituitary adenylate cyclase-activating polypeptide type 1 receptor IPR002285
- PACAPR (ADCYAP1R1)
Calcitonin receptor IPR003287
- CALCR
Corticotropin-releasing hormone receptor IPR003051
- CRHR1; CRHR2
Glucose-dependent insulinotropic polypeptide receptor/Gastric inhibitory polypeptide receptor IPR001749
- GIPR
Glucagon receptor-related IPR003290
- GLP1R; GLP2R;
Growth hormone releasing hormone receptor IPR003288
- GHRHR
Parathyroid hormone receptor IPR002170
- PTHR1; PTHR2
Secretin receptor IPR002144
- SCTR
Vasoactive intestinal peptide receptor IPR001571
- VIPR1; VIPR2

[edit] Subfamily B2

Subfamily B2 contains receptors with long extracellular N-termini, such as the leukocyte cell-surface antigen CD97; calcium-independent receptors for latrotoxin (such as O94910, and brain-specific angiogenesis inhibitor receptors (such as O14514) amongst others.

Brain-specific angiogenesis inhibitor IPR008077
- BAI1; BAI2; BAI3
CD97 antigen IPR003056
- CD97
EMR hormone receptor IPR001740
- CELSR1; CELSR2; CELSR3; EMR1; EMR2; EMR3; EMR4
GPR56 orphan receptor IPR003910
- GPR56; GPR64; GPR97; GPR110; GPR111; GPR112; GPR113; GPR114; GPR115; GPR123; GPR125; GPR126; GPR128; GPR133; GPR144; GPR157
Latrophilin receptor IPR003924
- ELTD1; LPHN1; LPHN2; LPHN3

[edit] Subfamily B3

Subfamily B3 includes Methuselah and other Drosophila proteins. Other than the typical seven-transmembrane region, characteristic structural features include an amino-terminal extracellular domain involved in ligand binding, and an intracellular loop (IC3) required for specific G-protein coupling.

Diuretic hormone receptor IPR002001

[edit] Unclassified subfamilies

Ig-hepta receptor IPR008078
- GPR116

[edit] Unclassified members

HCTR-5; HCTR-6; KPG_006; KPG_008

[edit] References

^ PDB 1BL1; Pellegrini M, Bisello A, Rosenblatt M, Chorev M, Mierke DF (September 1998). "Binding domain of human parathyroid hormone receptor: from conformation to function". Biochemistry 37 (37): 12737–43. doi:10.1021/bi981265h. PMID 9737850.
^ Harmar AJ (2001). "Family-B G-protein-coupled receptors". Genome Biol. 2 (12): REVIEWS3013. doi:10.1186/gb-2001-2-12-reviews3013. PMC 138994. PMID 11790261. //www.ncbi.nlm.nih.gov/pmc/articles/PMC138994/.

Cell surface receptor: G protein-coupled receptors

Class A:
Rhodopsin like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3

Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)

Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)

Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine (D1 D2 D3 D4 D5) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 (1 2) FPRL1 OXE Prostaglandin (DP (1 2), EP (1 2 3 4), FP) Prostacyclin Thromboxane

Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide	B/W (1 2) FF (1 2) S Y (1 2 4 5) Neuromedin (B U (1 2)) Neurotensin (1 2)

Other	Anaphylatoxin (C3a C5a) Angiotensin (1 2) Apelin Bombesin (BRS3 GRPR NMBR) Bradykinin (B1 B2) Chemokine Cholecystokinin (A B) Endothelin (A B) Formyl peptide (1 2 3) FSH Galanin (1 2 3) GHB receptor Gonadotropin-releasing hormone (1 2) Ghrelin Kisspeptin Luteinizing hormone/choriogonadotropin MAS (1 1L D E F G X1 X2 X3 X4) Melanocortin (1 2 3 4 5) MCHR (1 2) Motilin Opioid (Delta Kappa Mu Nociceptin & Zeta, but not Sigma) Orexin (1 2) Oxytocin Prokineticin (1 2) Prolactin-releasing peptide Relaxin (1 2 3 4) Somatostatin (1 2 3 4 5) Tachykinin (1 2 3) Thyrotropin Thyrotropin-releasing hormone Urotensin-II Vasopressin (1A 1B 2)

Miscellaneous

Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 77 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)

Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin like

Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)

Other	Brain-specific angiogenesis inhibitor (1 2 3) Cadherin (1 2 3) Calcitonin CALCRL CD97 Corticotropin-releasing hormone (1 2) EMR (1 2 3) Glucagon (GR GIPR GLP1R GLP2R) Growth hormone releasing hormone PACAPR1 GPR Latrophilin (1 2 3 ELTD1) Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic
glutamate / pheromone

Taste	TAS1R (1 2 3) TAS2R (1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60)

Other	Calcium-sensing receptor GABA B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)

Class F:
Frizzled / Smoothened

Frizzled	Frizzled (1 2 3 4 5 6 7 8 9 10)

Smoothened	Smoothened

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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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.

7 transmembrane receptor (Secretin family) Provide feedback

This family is known as Family B, the secretin-receptor family or family 2 of the G-protein-coupled receptors (GCPRs).They have been described in many animal species, but not in plants, fungi or prokaryotes. Three distinct sub-families are recognised. Subfamily B1 contains classical hormone receptors, such as receptors for secretin and glucagon, that are all involved in cAMP-mediated signalling pathways. Subfamily B2 contains receptors with long extracellular N-termini, such as the leukocyte cell-surface antigen CD97 (P48960); calcium-independent receptors for latrotoxin (such as O94910), and brain-specific angiogenesis inhibitors (such as O14514) amongst others. Subfamily B3 includes Methuselah and other Drosophila proteins (e.g. P83119). Other than the typical seven-transmembrane region, characteristic structural features include an amino-terminal extracellular domain involved in ligand binding, and an intracellular loop (IC3) required for specific G-protein coupling [1].

Literature references

Harmar AJ; , Genome Biol 2001;2:REVIEWS3013.: Family-B G-protein-coupled receptors. PUBMED:11790261 EPMC:11790261

External database links

PANDIT:	PF00002
PROSITE:	PDOC00559
Pseudofam:	PF00002
SCOP:	1bl1
SYSTERS:	7tm_2

This tab holds annotation information from the InterPro database.

InterPro entry IPR000832

G-protein-coupled receptors, GPCRs, constitute a vast protein family that encompasses a wide range of functions (including various autocrine, paracrine and endocrine processes). They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups. We use the term clan to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [PUBMED:8170923]. The currently known clan members include the rhodopsin-like GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating pheromone receptors, and the metabotropic glutamate receptor family. There is a specialised database for GPCRs (http://www.gpcr.org/7tm/).

The secretin-like GPCRs include secretin [PUBMED:1646711], calcitonin [PUBMED:1658940], parathyroid hormone/parathyroid hormone-related peptides [PUBMED:1658941] and vasoactive intestinal peptide [PUBMED:1314625], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N terminus is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allow the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.

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	G-protein coupled receptor activity (GO:0004930)
Biological process	G-protein coupled receptor signaling pathway (GO:0007186)

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 GPCR_A (CL0192), which contains the following 35 members:

7TM-7TMR_HD 7tm_1 7tm_2 7tm_4 7TM_GPCR_Sra 7TM_GPCR_Srab 7TM_GPCR_Srb 7TM_GPCR_Srbc 7TM_GPCR_Srd 7TM_GPCR_Srh 7TM_GPCR_Sri 7TM_GPCR_Srj 7TM_GPCR_Srsx 7TM_GPCR_Srt 7TM_GPCR_Sru 7TM_GPCR_Srv 7TM_GPCR_Srw 7TM_GPCR_Srx 7TM_GPCR_Srz 7TM_GPCR_Str Bac_rhodopsin Dicty_CAR DUF1182 DUF621 Frizzled Git3 Git3_C GpcrRhopsn4 Lung_7-TM_R Ocular_alb Serpentine_r_xa Sre Srg TAS2R V1R

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 (31)	Full (4718)	Representative proteomes				NCBI (4248)	Meta (5)
	Seed (31)	Full (4718)	RP15 (852)	RP35 (1057)	RP55 (1672)	RP75 (2544)	NCBI (4248)	Meta (5)
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 (31)	Full (4718)	Representative proteomes				NCBI (4248)	Meta (5)
	Seed (31)	Full (4718)	RP15 (852)	RP35 (1057)	RP55 (1672)	RP75 (2544)	NCBI (4248)	Meta (5)
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 (31)	Full (4718)	Representative proteomes				NCBI (4248)	Meta (5)
	Seed (31)	Full (4718)	RP15 (852)	RP35 (1057)	RP55 (1672)	RP75 (2544)	NCBI (4248)	Meta (5)
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:

Prosite

Previous IDs:

none

Type:

Family

Author:

Sonnhammer ELL

Number in seed:

31

Number in full:

4718

Average length of the domain:

225.10 aa

Average identity of full alignment:

22 %

Average coverage of the sequence by the domain:

28.73 %

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:

243

Family (HMM) version:

19

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

Sunburst controls

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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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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:

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highlight species that are represented in the seed alignment
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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 7tm_2 domain has been found. There are 3 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: 7tm_2 (PF00002)

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