2k9y: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
(9 intermediate revisions by the same user not shown)
Line 1: Line 1:
{{Seed}}
[[Image:2k9y.jpg|left|200px]]


<!--
==EphA2 dimeric structure in the lipidic bicelle at pH 5.0==
The line below this paragraph, containing "STRUCTURE_2k9y", creates the "Structure Box" on the page.
<StructureSection load='2k9y' size='340' side='right'caption='[[2k9y]]' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2k9y]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K9Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K9Y FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2k9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k9y OCA], [https://pdbe.org/2k9y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k9y RCSB], [https://www.ebi.ac.uk/pdbsum/2k9y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k9y ProSAT]</span></td></tr>
{{STRUCTURE_2k9y|  PDB=2k9y  |  SCENE= }}
</table>
== Disease ==
[https://www.uniprot.org/uniprot/EPHA2_HUMAN EPHA2_HUMAN] Genetic variations in EPHA2 are the cause of susceptibility to cataract cortical age-related type 2 (ARCC2) [MIM:[https://omim.org/entry/613020 613020]. A developmental punctate opacity common in the cortex and present in most lenses. The cataract is white or cerulean, increases in number with age, but rarely affects vision.<ref>PMID:19573808</ref> <ref>PMID:19649315</ref>  Defects in EPHA2 are the cause of cataract posterior polar type 1 (CTPP1) [MIM:[https://omim.org/entry/116600 116600]. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.<ref>PMID:19573808</ref> <ref>PMID:19005574</ref> <ref>PMID:19306328</ref> <ref>PMID:22570727</ref>  Note=Overexpressed in several cancer types and promotes malignancy.<ref>PMID:19573808</ref>
== Function ==
[https://www.uniprot.org/uniprot/EPHA2_HUMAN EPHA2_HUMAN] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A 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. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.<ref>PMID:10655584</ref> <ref>PMID:16236711</ref> <ref>PMID:18339848</ref> <ref>PMID:19573808</ref> <ref>PMID:20679435</ref> <ref>PMID:20861311</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands control a diverse array of cell-cell interactions in the developing and adult organisms. During signal transduction across plasma membrane, Eph receptors, like other receptor tyrosine kinases, are involved in lateral dimerization and subsequent oligomerization presumably with proper assembly of their single-span transmembrane domains. Spatial structure of dimeric transmembrane domain of EphA2 receptor embedded into lipid bicelle was obtained by solution NMR, showing a left-handed parallel packing of the transmembrane helices (535-559)(2). The helices interact through the extended heptad repeat motif L(535)X(3)G(539)X(2)A(542)X(3)V(546)X(2)L(549) assisted by intermolecular stacking interactions of aromatic rings of (FF(557))(2), whereas the characteristic tandem GG4-like motif A(536)X(3)G(540)X(3)G(544) is not used, enabling another mode of helix-helix association. Importantly, a similar motif AX(3)GX(3)G as was found is responsible for right-handed dimerization of transmembrane domain of the EphA1 receptor. These findings serve as an instructive example of the diversity of transmembrane domain formation within the same family of protein kinases and seem to favor the assumption that the so-called rotation-coupled activation mechanism may take place during the Eph receptor signaling. A possible role of membrane lipid rafts in relation to Eph transmembrane domain oligomerization and Eph signal transduction was also discussed.


===EphA2 dimeric structure in the lipidic bicelle at pH 5.0===
Left-handed dimer of EphA2 transmembrane domain: Helix packing diversity among receptor tyrosine kinases.,Bocharov EV, Mayzel ML, Volynsky PE, Mineev KS, Tkach EN, Ermolyuk YS, Schulga AA, Efremov RG, Arseniev AS Biophys J. 2010 Mar 3;98(5):881-9. PMID:20197042<ref>PMID:20197042</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2k9y" style="background-color:#fffaf0;"></div>


==About this Structure==
==See Also==
2K9Y is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K9Y OCA].
*[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Arseniev, A S.]]
[[Category: Arseniev AS]]
[[Category: Bocharov, E V.]]
[[Category: Bocharov EV]]
[[Category: Mayzel, M L.]]
[[Category: Mayzel ML]]
[[Category: Volynsky, P E.]]
[[Category: Volynsky PE]]
[[Category: Atp-binding]]
[[Category: Dimeric transmembrane domain]]
[[Category: Ephrin receptor]]
[[Category: Glycoprotein]]
[[Category: Kinase]]
[[Category: Membrane]]
[[Category: Membrane protein]]
[[Category: Nucleotide-binding]]
[[Category: Phosphoprotein]]
[[Category: Polymorphism]]
[[Category: Receptor]]
[[Category: Receptor tyrosine kinase]]
[[Category: Transferase]]
[[Category: Transmembrane]]
[[Category: Tyrosine-protein kinase]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Aug 12 13:38:42 2009''

Latest revision as of 15:50, 20 December 2023

EphA2 dimeric structure in the lipidic bicelle at pH 5.0EphA2 dimeric structure in the lipidic bicelle at pH 5.0

Structural highlights

2k9y is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

EPHA2_HUMAN Genetic variations in EPHA2 are the cause of susceptibility to cataract cortical age-related type 2 (ARCC2) [MIM:613020. A developmental punctate opacity common in the cortex and present in most lenses. The cataract is white or cerulean, increases in number with age, but rarely affects vision.[1] [2] Defects in EPHA2 are the cause of cataract posterior polar type 1 (CTPP1) [MIM:116600. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.[3] [4] [5] [6] Note=Overexpressed in several cancer types and promotes malignancy.[7]

Function

EPHA2_HUMAN Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A 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. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.[8] [9] [10] [11] [12] [13]

Publication Abstract from PubMed

The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands control a diverse array of cell-cell interactions in the developing and adult organisms. During signal transduction across plasma membrane, Eph receptors, like other receptor tyrosine kinases, are involved in lateral dimerization and subsequent oligomerization presumably with proper assembly of their single-span transmembrane domains. Spatial structure of dimeric transmembrane domain of EphA2 receptor embedded into lipid bicelle was obtained by solution NMR, showing a left-handed parallel packing of the transmembrane helices (535-559)(2). The helices interact through the extended heptad repeat motif L(535)X(3)G(539)X(2)A(542)X(3)V(546)X(2)L(549) assisted by intermolecular stacking interactions of aromatic rings of (FF(557))(2), whereas the characteristic tandem GG4-like motif A(536)X(3)G(540)X(3)G(544) is not used, enabling another mode of helix-helix association. Importantly, a similar motif AX(3)GX(3)G as was found is responsible for right-handed dimerization of transmembrane domain of the EphA1 receptor. These findings serve as an instructive example of the diversity of transmembrane domain formation within the same family of protein kinases and seem to favor the assumption that the so-called rotation-coupled activation mechanism may take place during the Eph receptor signaling. A possible role of membrane lipid rafts in relation to Eph transmembrane domain oligomerization and Eph signal transduction was also discussed.

Left-handed dimer of EphA2 transmembrane domain: Helix packing diversity among receptor tyrosine kinases.,Bocharov EV, Mayzel ML, Volynsky PE, Mineev KS, Tkach EN, Ermolyuk YS, Schulga AA, Efremov RG, Arseniev AS Biophys J. 2010 Mar 3;98(5):881-9. PMID:20197042[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  2. ↑ Jun G, Guo H, Klein BE, Klein R, Wang JJ, Mitchell P, Miao H, Lee KE, Joshi T, Buck M, Chugha P, Bardenstein D, Klein AP, Bailey-Wilson JE, Gong X, Spector TD, Andrew T, Hammond CJ, Elston RC, Iyengar SK, Wang B. EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS Genet. 2009 Jul;5(7):e1000584. doi: 10.1371/journal.pgen.1000584. Epub 2009 , Jul 31. PMID:19649315 doi:10.1371/journal.pgen.1000584
  3. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  4. ↑ Shiels A, Bennett TM, Knopf HL, Maraini G, Li A, Jiao X, Hejtmancik JF. The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis. 2008;14:2042-55. Epub 2008 Nov 12. PMID:19005574
  5. ↑ Zhang T, Hua R, Xiao W, Burdon KP, Bhattacharya SS, Craig JE, Shang D, Zhao X, Mackey DA, Moore AT, Luo Y, Zhang J, Zhang X. Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract. Hum Mutat. 2009 May;30(5):E603-11. doi: 10.1002/humu.20995. PMID:19306328 doi:10.1002/humu.20995
  6. ↑ Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R. Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS One. 2012;7(5):e36564. doi: 10.1371/journal.pone.0036564. Epub 2012 May 3. PMID:22570727 doi:10.1371/journal.pone.0036564
  7. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  8. ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
  9. ↑ Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005 Dec 23;280(51):42375-82. Epub 2005 Oct 18. PMID:16236711 doi:10.1074/jbc.M503786200
  10. ↑ Zhang G, Njauw CN, Park JM, Naruse C, Asano M, Tsao H. EphA2 is an essential mediator of UV radiation-induced apoptosis. Cancer Res. 2008 Mar 15;68(6):1691-6. doi: 10.1158/0008-5472.CAN-07-2372. PMID:18339848 doi:10.1158/0008-5472.CAN-07-2372
  11. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  12. ↑ Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol. 2010 Aug 9;190(3):461-77. doi: 10.1083/jcb.201005141. Epub 2010 Aug , 2. PMID:20679435 doi:10.1083/jcb.201005141
  13. ↑ Lin S, Gordon K, Kaplan N, Getsios S. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1. Mol Biol Cell. 2010 Nov 15;21(22):3902-14. doi: 10.1091/mbc.E10-03-0242. Epub, 2010 Sep 22. PMID:20861311 doi:10.1091/mbc.E10-03-0242
  14. ↑ Bocharov EV, Mayzel ML, Volynsky PE, Mineev KS, Tkach EN, Ermolyuk YS, Schulga AA, Efremov RG, Arseniev AS. Left-handed dimer of EphA2 transmembrane domain: Helix packing diversity among receptor tyrosine kinases. Biophys J. 2010 Mar 3;98(5):881-9. PMID:20197042 doi:10.1016/j.bpj.2009.11.008
Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=2k9y&oldid=4002249"