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| | ==Ligand-receptor complex.== | | ==Ligand-receptor complex.== |
| - | <StructureSection load='5mr5' size='340' side='right' caption='[[5mr5]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='5mr5' size='340' side='right'caption='[[5mr5]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mr5]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MR5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MR5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mr5]] is a 4 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=5MR5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MR5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NRTN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GFRA2, GDNFRB, RETL2, TRNR2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5mr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mr5 OCA], [http://pdbe.org/5mr5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mr5 RCSB], [http://www.ebi.ac.uk/pdbsum/5mr5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mr5 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=5mr5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mr5 OCA], [https://pdbe.org/5mr5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mr5 RCSB], [https://www.ebi.ac.uk/pdbsum/5mr5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mr5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/NRTN_HUMAN NRTN_HUMAN]] Hirschsprung disease. Genetic variations in NRTN may contribute to Hirschsprung disease, in association with mutations of RET gene, and possibly mutations in other loci. Hirschsprung disease is a disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.<ref>PMID:9700200</ref> | + | [https://www.uniprot.org/uniprot/NRTN_HUMAN NRTN_HUMAN] Hirschsprung disease. Genetic variations in NRTN may contribute to Hirschsprung disease, in association with mutations of RET gene, and possibly mutations in other loci. Hirschsprung disease is a disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.<ref>PMID:9700200</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NRTN_HUMAN NRTN_HUMAN]] Supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Might control the size of non-neuronal cell population such as haemopoietic cells. [[http://www.uniprot.org/uniprot/GFRA2_HUMAN GFRA2_HUMAN]] Receptor for neurturin. Mediates the NRTN-induced autophosphorylation and activation of the RET receptor. Also able to mediate GDNF signaling through the RET tyrosine kinase receptor. Isoform 2: participates in NRTN-induced 'Ser-727' phosphorylation of STAT3.[UniProtKB:O08842] | + | [https://www.uniprot.org/uniprot/NRTN_HUMAN NRTN_HUMAN] Supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Might control the size of non-neuronal cell population such as haemopoietic cells. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Aagaard, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Dahl, G]] | + | [[Category: Aagaard A]] |
| - | [[Category: Oster, L]] | + | [[Category: Dahl G]] |
| - | [[Category: Roth, R]] | + | [[Category: Oster L]] |
| - | [[Category: Sandmark, J]] | + | [[Category: Roth R]] |
| - | [[Category: Complex]]
| + | [[Category: Sandmark J]] |
| - | [[Category: Ligand-receptor complex]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Signalling]]
| + | |
| Structural highlights
Disease
NRTN_HUMAN Hirschsprung disease. Genetic variations in NRTN may contribute to Hirschsprung disease, in association with mutations of RET gene, and possibly mutations in other loci. Hirschsprung disease is a disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.[1]
Function
NRTN_HUMAN Supports the survival of sympathetic neurons in culture. May regulate the development and maintenance of the CNS. Might control the size of non-neuronal cell population such as haemopoietic cells.
Publication Abstract from PubMed
Neurturin (NRTN) provides trophic support to neurons and is considered a therapeutic agent for neurodegenerative diseases, such as Parkinson's disease. It binds to its co-receptor GFRa2 and the resulting NRTN:GFRa2 complex activates the transmembrane receptors RET or NCAM. We report the crystal structure of NRTN, alone and in complex with GFRa2. This is the first crystal structure of a GFRa with all three domains and shows that domain 1 does not interact directly with NRTN, but may support an interaction with RET and/or NCAM, via a highly conserved surface. In addition, biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. We have identified a heparan sulfate binding site on NRTN and a putative binding site in GFRa2, suggesting that heparan sulfate has a role in assembly of the signalling complex. We further show that mutant NRTN with reduced affinity for heparan sulfate may provide a route forward for delivery of NRTN with increased exposure in preclinical in vivo models and ultimately to Parkinson's patients.
Structure and biophysical characterisation of the human full-length Neurturin-GFRa2 complex - a role for heparan sulfate in signalling.,Sandmark J, Dahl G, Oster L, Xu B, Johansson P, Akerud T, Aagaard A, Davidsson P, Bigalke JM, Sorhede-Winzell M, Rainey GJ, Roth RG J Biol Chem. 2018 Feb 2. pii: RA117.000820. doi: 10.1074/jbc.RA117.000820. PMID:29414779[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attie T, Bachy B, Munnich A, Lyonnet S. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998 Sep;7(9):1449-52. PMID:9700200
- ↑ Sandmark J, Dahl G, Oster L, Xu B, Johansson P, Akerud T, Aagaard A, Davidsson P, Bigalke JM, Sorhede-Winzell M, Rainey GJ, Roth RG. Structure and biophysical characterisation of the human full-length Neurturin-GFRa2 complex - a role for heparan sulfate in signalling. J Biol Chem. 2018 Feb 2. pii: RA117.000820. doi: 10.1074/jbc.RA117.000820. PMID:29414779 doi:http://dx.doi.org/10.1074/jbc.RA117.000820
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