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| | <SX load='6q2n' size='340' side='right' viewer='molstar' caption='[[6q2n]], [[Resolution|resolution]] 4.40Å' scene=''> | | <SX load='6q2n' size='340' side='right' viewer='molstar' caption='[[6q2n]], [[Resolution|resolution]] 4.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6q2n]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q2N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q2N FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6q2n]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q2N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q2N FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.4Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6q2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q2n OCA], [http://pdbe.org/6q2n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q2n RCSB], [http://www.ebi.ac.uk/pdbsum/6q2n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q2n ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6q2n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q2n OCA], [https://pdbe.org/6q2n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q2n RCSB], [https://www.ebi.ac.uk/pdbsum/6q2n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q2n ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GDNF_HUMAN GDNF_HUMAN]] Defects in GDNF may be a cause of Hirschsprung disease type 3 (HSCR3) [MIM:[http://omim.org/entry/613711 613711]]. In association with mutations of RET gene, defects in GDNF may be involved in Hirschsprung disease. This genetic disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.<ref>PMID:8968758</ref> <ref>PMID:8896568</ref> <ref>PMID:8896569</ref> <ref>PMID:10917288</ref> Defects in GDNF are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:[http://omim.org/entry/209880 209880]]; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.<ref>PMID:9497256</ref> [[http://www.uniprot.org/uniprot/RET_HUMAN RET_HUMAN]] Unilateral renal dysplasia;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia type 2B;Multiple endocrine neoplasia type 2A;Hirschsprung disease;Bilateral renal agenesis;Bilateral renal dysplasia;Ondine syndrome;Papillary or follicular thyroid carcinoma. Colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry. Hirschsprung disease 1 (HSCR1) [MIM:[http://omim.org/entry/142623 142623]]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:7704557</ref> <ref>PMID:7881414</ref> <ref>PMID:8114938</ref> <ref>PMID:8114939</ref> <ref>PMID:7633441</ref> <ref>PMID:7581377</ref> <ref>PMID:8595427</ref> <ref>PMID:9043870</ref> <ref>PMID:9090527</ref> <ref>PMID:9259198</ref> <ref>PMID:9094028</ref> <ref>PMID:9384613</ref> <ref>PMID:10090908</ref> <ref>PMID:10484767</ref> <ref>PMID:10618407</ref> <ref>PMID:22174939</ref> Medullary thyroid carcinoma (MTC) [MIM:[http://omim.org/entry/155240 155240]]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:7881414</ref> <ref>PMID:9259198</ref> <ref>PMID:7849720</ref> <ref>PMID:7874109</ref> <ref>PMID:8625130</ref> <ref>PMID:7845675</ref> <ref>PMID:7784092</ref> <ref>PMID:8557249</ref> <ref>PMID:8807338</ref> <ref>PMID:9398735</ref> <ref>PMID:9223675</ref> <ref>PMID:9677065</ref> <ref>PMID:9452077</ref> <ref>PMID:9506724</ref> <ref>PMID:9621513</ref> <ref>PMID:10323403</ref> <ref>PMID:10826520</ref> <ref>PMID:11692159</ref> Multiple neoplasia 2B (MEN2B) [MIM:[http://omim.org/entry/162300 162300]]: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophtalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:8625130</ref> <ref>PMID:8807338</ref> <ref>PMID:9223675</ref> <ref>PMID:7911697</ref> <ref>PMID:7906866</ref> <ref>PMID:7906417</ref> <ref>PMID:8595427</ref> <ref>PMID:9360560</ref> <ref>PMID:9294615</ref> Pheochromocytoma (PCC) [MIM:[http://omim.org/entry/171300 171300]]: A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:[http://omim.org/entry/171400 171400]]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:7881414</ref> <ref>PMID:9384613</ref> <ref>PMID:7874109</ref> <ref>PMID:8625130</ref> <ref>PMID:8807338</ref> <ref>PMID:9223675</ref> <ref>PMID:9621513</ref> <ref>PMID:8103403</ref> <ref>PMID:8099202</ref> <ref>PMID:7915165</ref> <ref>PMID:7860065</ref> <ref>PMID:8626834</ref> <ref>PMID:9097963</ref> <ref>PMID:9452064</ref> <ref>PMID:10522989</ref> Thyroid papillary carcinoma (TPC) [MIM:[http://omim.org/entry/188550 188550]]: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving RET have been found in thyroid papillary carcinomas. Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene; inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene; translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene; translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion; translocation t(6;10)(p21.3;q11.2) with RFP generates the Delta RFP/RET oncogene; translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene; translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. The PTC5 oncogene has been found in 2 cases of PACT in children exposed to radioactive fallout after Chernobyl. A chromosomal aberration involving TRIM27/RFP is found in thyroid papillary carcinomas. Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes. Renal adysplasia (RADYS) [MIM:[http://omim.org/entry/191830 191830]]: Renal agenesis refers to the absence of one (unilateral) or both (bilateral) kidneys at birth. Bilateral renal agenesis belongs to a group of perinatally lethal renal diseases, including severe bilateral renal dysplasia, unilateral renal agenesis with contralateral dysplasia and severe obstructive uropathy. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:18252215</ref> Congenital central hypoventilation syndrome (CCHS) [MIM:[http://omim.org/entry/209880 209880]]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:9497256</ref> <ref>PMID:12086152</ref> <ref>PMID:14566559</ref> | + | [https://www.uniprot.org/uniprot/GDNF_HUMAN GDNF_HUMAN] Defects in GDNF may be a cause of Hirschsprung disease type 3 (HSCR3) [MIM:[https://omim.org/entry/613711 613711]. In association with mutations of RET gene, defects in GDNF may be involved in Hirschsprung disease. This genetic disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.<ref>PMID:8968758</ref> <ref>PMID:8896568</ref> <ref>PMID:8896569</ref> <ref>PMID:10917288</ref> Defects in GDNF are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:[https://omim.org/entry/209880 209880]; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.<ref>PMID:9497256</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GDNF_HUMAN GDNF_HUMAN]] Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.<ref>PMID:8493557</ref> [[http://www.uniprot.org/uniprot/RET_HUMAN RET_HUMAN]] Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration.<ref>PMID:20064382</ref> <ref>PMID:20616503</ref> <ref>PMID:20702524</ref> <ref>PMID:21357690</ref> <ref>PMID:21454698</ref> [[http://www.uniprot.org/uniprot/GFRA1_HUMAN GFRA1_HUMAN]] Receptor for GDNF. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor (By similarity). | + | [https://www.uniprot.org/uniprot/GDNF_HUMAN GDNF_HUMAN] Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.<ref>PMID:8493557</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Bai XC]] |
| - | [[Category: Bai, X C]] | + | [[Category: Brautigam CA]] |
| - | [[Category: Brautigam, C A]] | + | [[Category: Chen YJ]] |
| - | [[Category: Chen, Y J]] | + | [[Category: Li J]] |
| - | [[Category: Li, J]] | + | [[Category: Liou J]] |
| - | [[Category: Liou, J]] | + | [[Category: Shang GJ]] |
| - | [[Category: Shang, G J]] | + | [[Category: Zhang XW]] |
| - | [[Category: Zhang, X W]] | + | |
| - | [[Category: Cryo-em]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| - | [[Category: Ret]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Disease
GDNF_HUMAN Defects in GDNF may be a cause of Hirschsprung disease type 3 (HSCR3) [MIM:613711. In association with mutations of RET gene, defects in GDNF may be involved in Hirschsprung disease. This genetic disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.[1] [2] [3] [4] Defects in GDNF are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia.[5]
Function
GDNF_HUMAN Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.[6]
Publication Abstract from PubMed
RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ligands but also co-receptors for activation, the mechanisms of which remain unclear due to lack of high-resolution structures of the ligand/co-receptor/receptor complexes. Here, we report cryo-EM structures of the extracellular region ternary complexes of GDF15/GFRAL/RET, GDNF/GFRalpha1/RET, NRTN/GFRalpha2/RET and ARTN/GFRalpha3/RET. These structures reveal that all the four ligand/co-receptor pairs, while using different atomic interactions, induce a specific dimerization mode of RET that is poised to bring the two kinase domains into close proximity for cross-phosphorylation. The NRTN/GFRalpha2/RET dimeric complex further pack into a tetrameric assembly, which is shown by our cell-based assays to regulate the endocytosis of RET. Our analyses therefore reveal both the common mechanism and diversification in the activation of RET by different ligands.
Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands.,Li J, Shang G, Chen YJ, Brautigam CA, Liou J, Zhang X, Bai XC Elife. 2019 Sep 19;8. pii: 47650. doi: 10.7554/eLife.47650. PMID:31535977[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ivanchuk SM, Myers SM, Eng C, Mulligan LM. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Hum Mol Genet. 1996 Dec;5(12):2023-6. PMID:8968758
- ↑ Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996 Nov;14(3):341-4. PMID:8896568 doi:10.1038/ng1196-341
- ↑ Salomon R, Attie T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O, Ricour C, Nihoul-Fekete C, Munnich A, Lyonnet S. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nat Genet. 1996 Nov;14(3):345-7. PMID:8896569 doi:10.1038/ng1196-345
- ↑ Martucciello G, Ceccherini I, Lerone M, Jasonni V. Pathogenesis of Hirschsprung's disease. J Pediatr Surg. 2000 Jul;35(7):1017-25. PMID:10917288
- ↑ Amiel J, Salomon R, Attie T, Pelet A, Trang H, Mokhtari M, Gaultier C, Munnich A, Lyonnet S. Mutations of the RET-GDNF signaling pathway in Ondine's curse. Am J Hum Genet. 1998 Mar;62(3):715-7. PMID:9497256 doi:10.1086/301759
- ↑ Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993 May 21;260(5111):1130-2. PMID:8493557
- ↑ Li J, Shang G, Chen YJ, Brautigam CA, Liou J, Zhang X, Bai XC. Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. Elife. 2019 Sep 19;8. pii: 47650. doi: 10.7554/eLife.47650. PMID:31535977 doi:http://dx.doi.org/10.7554/eLife.47650
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