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| | ==Structure of the human EphA3 receptor ligand binding domain complexed with ephrin-A5== | | ==Structure of the human EphA3 receptor ligand binding domain complexed with ephrin-A5== |
| - | <StructureSection load='4l0p' size='340' side='right' caption='[[4l0p]], [[Resolution|resolution]] 2.26Å' scene=''> | + | <StructureSection load='4l0p' size='340' side='right'caption='[[4l0p]], [[Resolution|resolution]] 2.26Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4l0p]] is a 2 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=4L0P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L0P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4l0p]] is a 2 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=4L0P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L0P 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>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </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>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPHA3, EPHA3_HUMAN, ETK, ETK1, HEK, TYRO4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EFNA5, EFNA5_HUMAN, EPLG7, LERK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4l0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l0p OCA], [https://pdbe.org/4l0p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l0p RCSB], [https://www.ebi.ac.uk/pdbsum/4l0p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l0p ProSAT]</span></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=4l0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l0p OCA], [http://pdbe.org/4l0p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4l0p RCSB], [http://www.ebi.ac.uk/pdbsum/4l0p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4l0p ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN]] Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. | + | [https://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN] Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN]] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.<ref>PMID:11870224</ref> [[http://www.uniprot.org/uniprot/EFNA5_HUMAN EFNA5_HUMAN]] Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Induces compartmentalized signaling within a caveolae-like membrane microdomain when bound to the extracellular domain of its cognate receptor. This signaling event requires the activity of the Fyn tyrosine kinase. Activates the EPHA3 receptor to regulate cell-cell adhesion and cytoskeletal organization. With the receptor EPHA2 may regulate lens fiber cells shape and interactions and be important for lens transparency maintenance. May function actively to stimulate axon fasciculation. The interaction of EFNA5 with EPHA5 also mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion. Cognate/functional ligand for EPHA7, their interaction regulates brain development modulating cell-cell adhesion and repulsion.<ref>PMID:10601038</ref> <ref>PMID:11870224</ref> | + | [https://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.<ref>PMID:11870224</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4l0p" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4l0p" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ephrin|Ephrin]] |
| | + | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Forse, G J]] | + | [[Category: Large Structures]] |
| - | [[Category: Kolatkar, A R]] | + | [[Category: Forse GJ]] |
| - | [[Category: Kuhn, P]] | + | [[Category: Kolatkar AR]] |
| - | [[Category: Beta-sandwich]] | + | [[Category: Kuhn P]] |
| - | [[Category: Ephrin binding]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| - | [[Category: Transferase-transferase receptor complex]]
| + | |
| Structural highlights
Disease
EPHA3_HUMAN Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:114500.
Function
EPHA3_HUMAN Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.[1]
Publication Abstract from PubMed
The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins.
Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5.,Forse GJ, Uson ML, Nasertorabi F, Kolatkar A, Lamberto I, Pasquale EB, Kuhn P PLoS One. 2015 May 20;10(5):e0127081. doi: 10.1371/journal.pone.0127081., eCollection 2015. PMID:25993310[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lawrenson ID, Wimmer-Kleikamp SH, Lock P, Schoenwaelder SM, Down M, Boyd AW, Alewood PF, Lackmann M. Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling. J Cell Sci. 2002 Mar 1;115(Pt 5):1059-72. PMID:11870224
- ↑ Forse GJ, Uson ML, Nasertorabi F, Kolatkar A, Lamberto I, Pasquale EB, Kuhn P. Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5. PLoS One. 2015 May 20;10(5):e0127081. doi: 10.1371/journal.pone.0127081., eCollection 2015. PMID:25993310 doi:http://dx.doi.org/10.1371/journal.pone.0127081
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