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9  structures 53  species 0  interactions 186  sequences 4  architectures

Family: Endothelin (PF00322)

Summary: Endothelin family

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This is the Wikipedia entry entitled "Endothelin". More...

Endothelin Edit Wikipedia article

Endothelin family
1EDN human endothelin1 02.png
Identifiers
Symbol Endothelin
Pfam PF00322
InterPro IPR001928
PROSITE PDOC00243
SCOP 1edp
SUPERFAMILY 1edp
OPM superfamily 156
OPM protein 3cmh
Endothelin 1
Identifiers
Symbol EDN1
Entrez 1906
HUGO 3176
OMIM 131240
RefSeq NM_001955
UniProt P05305
Other data
Locus Chr. 6 p23-p24
Endothelin 2
Identifiers
Symbol EDN2
Entrez 1907
HUGO 3177
OMIM 131241
RefSeq NM_001956
UniProt P20800
Other data
Locus Chr. 1 p34
Endothelin 3
Identifiers
Symbol EDN3
HUGO 3178
OMIM 131242
RefSeq NM_000114
UniProt P14138
Other data
Locus Chr. 20 q13.2-q13.3

Endothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure (hypertension) and heart disease.

Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelins are implicated in vascular diseases of several organ systems, including the heart, general circulation and brain.[1][2]

Etymology[edit]

Endothelins derived the name from the fact that they were derived and secreted from cultured endothelial cells.[3]

Isoforms[edit]

There are three isoforms (identified as ET-1, -2, -3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC.[4]

Antagonists[edit]

Earliest antagonists discovered for ETA is BQ123, and that for ETB is BQ788.[3]

Examples of physiological interaction[edit]

Endothelins are the most potent vasoconstrictors known.[5] In a healthy individual, a delicate balance between vasoconstriction and vasodilation is maintained by endothelin and other vasoconstrictors on the one hand and nitric oxide, prostacyclin and other vasodilators on the other.

Overproduction of endothelin in the lungs may cause pulmonary hypertension, which can sometimes be treated by the use of an endothelin receptor antagonist, such as bosentan, sitaxentan or ambrisentan. The latter drug selectively blocks endothelin A receptors, decreasing the vasoconstrictive actions and allowing for increased beneficial effects of endothelin B stimulation, such as nitric oxide production. The precise effects of endothelin B receptor activation depends on the type of cells involved.

Disease involvement[edit]

The ubiquitous distribution of endothelin peptides and receptors implicates its involvement in a wide variety of physiological and pathological processes in the body. Among numerous diseases potentially occurring from endothelin dysregulation are

Gene regulation[edit]

The endothelium regulates local vascular tone and integrity through the coordinated release of vasoactive molecules. Secretion of endothelin-1 (ET-1)1 from the endothelium signals vasoconstriction and influences local cellular growth and survival. ET-1 has been implicated in the development and progression of vascular disorders such as atherosclerosis and hypertension. Endothelial cells upregulate ET-1 in response to hypoxia, oxidized LDL, pro-inflammatory cytokines, and bacterial toxins. Initial studies on the ET-1 promoter provided some of the earliest mechanistic insight into endothelial-specific gene regulation. Numerous studies have since provided valuable insight into ET-1 promoter regulation under basal and activated cellular states.

The ET-1 mRNA is labile with a half-life of less than an hour. Together, the combined actions of ET-1 transcription and rapid mRNA turnover allow for stringent control over its expression. It has previously been shown that ET-1 mRNA is selectively stabilized in response to cellular activation by Escherichia coli O157:H7-derived verotoxins, suggesting ET-1 is regulated by post-transcriptional mechanisms. Regulatory elements modulating mRNA half-life are often found within 3'-untranslated regions (3'-UTR). The 1.1-kb 3'-UTR of human ET-1 accounts for over 50% of the transcript length and features long tracts of highly conserved sequences including an AU-rich region. Some 3'-UTR AU-rich elements (AREs) play important regulatory roles in cytokine and proto-oncogene expression by influencing half-life under basal conditions and in response to cellular activation. Several RNA-binding proteins with affinities for AREs have been characterized including AUF1 (hnRNPD), the ELAV family (HuR, HuB, HuC, HuD), tristetraprolin, TIA/TIAR, HSP70, and others. Although specific mechanisms directing ARE activity have not been fully elucidated, current models suggest ARE-binding proteins target specific mRNAs to cellular pathways that influence 3'-polyadenylate tail and 5'-cap metabolism.

Recent studies have revealed a functional link between AUF1, heat shock proteins and the ubiquitin-proteasome network. Proteasome inhibition by chemical inhibition or heat shock was shown to stabilize a model ARE-containing mRNA whereas promotion of cellular ubiquitination pathways was shown to accelerate ARE mRNA turnover. Studies with in vitro proteasome preparations suggest that the proteasome itself may possess ARE-specific RNA destabilizing activity. The ARE-binding protein AUF1 has been linked to the ubiquitin-proteasome pathway. AUF1 mRNA destabilizing activity has been positively correlated with its level of polyubiquitination and has been shown to interact with a member of the E2 ubiquitin-conjugating protein family. Furthermore, under conditions of cellular heat shock AUF1 associates with heat shock protein 70 (HSP70), which itself possesses ARE binding activity.

The ET-1 transcript is constitutively destabilized by its 3'-UTR through two destabilizing elements, DE1 and DE2. DE1 functions through a conserved ARE by the AUF1-proteasome pathway and is regulated by the heat shock pathway.[9]

References[edit]

  1. ^ Agapitov AV, Haynes WG (March 2002). "Role of endothelin in cardiovascular disease". J Renin Angiotensin Aldosterone Syst 3 (1): 1–15. doi:10.3317/jraas.2002.001. PMID 11984741. 
  2. ^ Schinelli S (2006). "Pharmacology and physiopathology of the brain endothelin system: an overview". Curr. Med. Chem. 13 (6): 627–38. doi:10.2174/092986706776055652. PMID 16529555. 
  3. ^ a b Microcirculation (2nd ed. ed.). Amsterdam: Elsevier/Academic Press. 2008. pp. 305–307. ISBN 9780123745309. 
  4. ^ Medical physiology a cellular and molecular approach (2nd ed., International ed. ed.). Philadelphia, PA: Saunders/Elsevier. 2009. p. 480. ISBN 9781437720174. 
  5. ^ Modern pharmacology with clinical applications (6th ed. ed.). Philadelphia: Lippincott Williams & Wilkins. 2004. p. 215. ISBN 0781737621. 
  6. ^ Bagnato A, Rosanò L (2008). "The endothelin axis in cancer". Int. J. Biochem. Cell Biol. 40 (8): 1443–51. doi:10.1016/j.biocel.2008.01.022. PMID 18325824. 
  7. ^ Macdonald RL, Pluta RM, Zhang JH (May 2007). "Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution". Nat Clin Pract Neurol 3 (5): 256–63. doi:10.1038/ncpneuro0490. PMID 17479073. 
  8. ^ Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M (2005). "Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice". Neuroscience 130 (2): 349–58. doi:10.1016/j.neuroscience.2004.09.036. PMID 15664691. 
  9. ^ Mawji IA, Robb GB, Tai SC, Marsden PA (March 2004). "Role of the 3'-untranslated region of human endothelin-1 in vascular endothelial cells. Contribution to transcript lability and the cellular heat shock response". J. Biol. Chem. 279 (10): 8655–67. doi:10.1074/jbc.M312190200. PMID 14660616. 

Further reading[edit]

External links[edit]

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001928

Endothelins (ET's) are the most potent vasoconstrictors known [PUBMED:2690429, PUBMED:2168326, PUBMED:1916094]. They stimulate cardiac contraction, regulate release of vasoactive substances, and stimulate mitogenesis in blood vessels in primary culture. They also stimulate contraction in almost all other smooth muscles (e.g., uterus, bronchus, vas deferensa and stomach) and stimulate secretion in several tissues (e.g., kidney, liver and adrenals). Endothelin receptors have also been found in the brain, e.g. cerebral cortex, cerebellum and glial cells. Endothelins have been implicated in a variety of pathophysiological conditions associated with stress, including hypertension, myocardial infarction, subarachnoid haemorrhage and renal failure.

Endothelins are synthesised by proteolysis of large preproendothelins, which are cleaved to 'big endothelins' before being processed to the mature peptide.

Sarafotoxins (SRTX) and bibrotoxin (BTX) are cardiotoxins from the venom of snakes of the Atractaspis family, structurally and functionally [PUBMED:2549664, PUBMED:1656557] similar to endothelin.

As shown in the following schematic representation, these peptides which are 21 residues long contain two intramolecular disulphide bonds.

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

Gene Ontology

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Domain organisation

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(8)
Full
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Representative proteomes NCBI
(193)
Meta
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RP15
(3)
RP35
(9)
RP55
(26)
RP75
(79)
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  Seed
(8)
Full
(186)
Representative proteomes NCBI
(193)
Meta
(0)
RP15
(3)
RP35
(9)
RP55
(26)
RP75
(79)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: endothelin;
Type: Repeat
Author: Finn RD
Number in seed: 8
Number in full: 186
Average length of the domain: 29.50 aa
Average identity of full alignment: 68 %
Average coverage of the sequence by the domain: 19.48 %

HMM information View help on HMM parameters

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 20.5 20.5
Trusted cut-off 25.3 20.5
Noise cut-off 19.7 20.3
Model length: 31
Family (HMM) version: 12
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Species distribution

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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 Endothelin domain has been found. There are 9 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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