6q2n

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of RET/GFRa1/GDNF extracellular complex

6q2n, resolution 4.40Å

Structural highlights

6q2n is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.4Å
Ligands:
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6q2n"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6q2n is ON HOLD
+==Cryo-EM structure of RET/GFRa1/GDNF extracellular complex==
+<SX load='6q2n' size='340' side='right' viewer='molstar' caption='[[6q2n]], [[Resolution|resolution]] 4.40&Aring;' scene=''>
+== Structural highlights ==
+<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.4&#8491;</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'>[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>
+== Disease ==
+[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 ==
+[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;">
+== 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.
-Authors:
+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<ref>PMID:31535977</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6q2n" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</SX>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bai XC]]
+[[Category: Brautigam CA]]
+[[Category: Chen YJ]]
+[[Category: Li J]]
+[[Category: Liou J]]
+[[Category: Shang GJ]]
+[[Category: Zhang XW]]

6q2n

From Proteopedia

Current revision

Cryo-EM structure of RET/GFRa1/GDNF extracellular complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox