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[[Image:2gy7.gif|left|200px]]


{{Structure
==Angiopoietin-2/Tie2 Complex Crystal Structure==
|PDB= 2gy7 |SIZE=350|CAPTION= <scene name='initialview01'>2gy7</scene>, resolution 3.700&Aring;
<StructureSection load='2gy7' size='340' side='right'caption='[[2gy7]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
<table><tr><td colspan='2'>[[2gy7]] 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=2GY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GY7 FirstGlance]. <br>
|ACTIVITY= <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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.7&#8491;</td></tr>
|GENE= TEK, TIE2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<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=NDG:2-(ACETYLAMINO)-2-DEOXY-A-D-GLUCOPYRANOSE'>NDG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2gy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gy7 OCA], [https://pdbe.org/2gy7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gy7 RCSB], [https://www.ebi.ac.uk/pdbsum/2gy7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gy7 ProSAT]</span></td></tr>
|RELATEDENTRY=[[2gy5|2GY5]], [[1z3s|1Z3S]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2gy7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gy7 OCA], [http://www.ebi.ac.uk/pdbsum/2gy7 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2gy7 RCSB]</span>
== Disease ==
}}
[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:[https://omim.org/entry/600195 600195]; an error of vascular morphogenesis characterized by dilated, serpiginous channels.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> <ref>PMID:8980225</ref> <ref>PMID:10369874</ref> <ref>PMID:19888299</ref>  Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
 
== Function ==
'''Angiopoietin-2/Tie2 Complex Crystal Structure'''
[https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.<ref>PMID:9204896</ref> <ref>PMID:12816861</ref> <ref>PMID:15284220</ref> <ref>PMID:14665640</ref> <ref>PMID:15851516</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref> <ref>PMID:19223473</ref> <ref>PMID:18366015</ref> <ref>PMID:20651738</ref>
 
== Evolutionary Conservation ==
 
[[Image:Consurf_key_small.gif|200px|right]]
==Overview==
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gy/2gy7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2gy7 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Tie receptor tyrosine kinases and their angiopoietin (Ang) ligands play central roles in developmental and tumor-induced angiogenesis. Here we present the crystal structures of the Tie2 ligand-binding region alone and in complex with Ang2. In contrast to prediction, Tie2 contains not two but three immunoglobulin (Ig) domains, which fold together with the three epidermal growth factor domains into a compact, arrowhead-shaped structure. Ang2 binds at the tip of the arrowhead utilizing a lock-and-key mode of ligand recognition-unique for a receptor kinase-where two complementary surfaces interact with each other with no domain rearrangements and little conformational change in either molecule. Ang2-Tie2 recognition is similar to antibody-protein antigen recognition, including the location of the ligand-binding site within the Ig fold. Analysis of the structures and structure-based mutagenesis provide insight into the mechanism of receptor activation and support the hypothesis that all angiopoietins interact with Tie2 in a structurally similar manner.
The Tie receptor tyrosine kinases and their angiopoietin (Ang) ligands play central roles in developmental and tumor-induced angiogenesis. Here we present the crystal structures of the Tie2 ligand-binding region alone and in complex with Ang2. In contrast to prediction, Tie2 contains not two but three immunoglobulin (Ig) domains, which fold together with the three epidermal growth factor domains into a compact, arrowhead-shaped structure. Ang2 binds at the tip of the arrowhead utilizing a lock-and-key mode of ligand recognition-unique for a receptor kinase-where two complementary surfaces interact with each other with no domain rearrangements and little conformational change in either molecule. Ang2-Tie2 recognition is similar to antibody-protein antigen recognition, including the location of the ligand-binding site within the Ig fold. Analysis of the structures and structure-based mutagenesis provide insight into the mechanism of receptor activation and support the hypothesis that all angiopoietins interact with Tie2 in a structurally similar manner.


==About this Structure==
Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.,Barton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP, Nikolov DB Nat Struct Mol Biol. 2006 Jun;13(6):524-32. Epub 2006 May 28. PMID:16732286<ref>PMID:16732286</ref>
2GY7 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GY7 OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex., Barton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP, Nikolov DB, Nat Struct Mol Biol. 2006 Jun;13(6):524-32. Epub 2006 May 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16732286 16732286]
</div>
<div class="pdbe-citations 2gy7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Barton WA]]
[[Category: Barton, W A.]]
[[Category: Nikolov DB]]
[[Category: Nikolov, D B.]]
[[Category: receptor-ligand complex]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:22:58 2008''

Latest revision as of 12:45, 25 December 2024

Angiopoietin-2/Tie2 Complex Crystal StructureAngiopoietin-2/Tie2 Complex Crystal Structure

Structural highlights

2gy7 is a 2 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:X-ray diffraction, Resolution 3.7Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TIE2_HUMAN Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:600195; an error of vascular morphogenesis characterized by dilated, serpiginous channels.[1] [2] [3] [4] [5] Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.[6] [7]

Function

TIE2_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The Tie receptor tyrosine kinases and their angiopoietin (Ang) ligands play central roles in developmental and tumor-induced angiogenesis. Here we present the crystal structures of the Tie2 ligand-binding region alone and in complex with Ang2. In contrast to prediction, Tie2 contains not two but three immunoglobulin (Ig) domains, which fold together with the three epidermal growth factor domains into a compact, arrowhead-shaped structure. Ang2 binds at the tip of the arrowhead utilizing a lock-and-key mode of ligand recognition-unique for a receptor kinase-where two complementary surfaces interact with each other with no domain rearrangements and little conformational change in either molecule. Ang2-Tie2 recognition is similar to antibody-protein antigen recognition, including the location of the ligand-binding site within the Ig fold. Analysis of the structures and structure-based mutagenesis provide insight into the mechanism of receptor activation and support the hypothesis that all angiopoietins interact with Tie2 in a structurally similar manner.

Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex.,Barton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP, Nikolov DB Nat Struct Mol Biol. 2006 Jun;13(6):524-32. Epub 2006 May 28. PMID:16732286[18]

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

References

  1. ↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
  2. ↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
  3. ↑ Vikkula M, Boon LM, Carraway KL 3rd, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996 Dec 27;87(7):1181-90. PMID:8980225
  4. ↑ Calvert JT, Riney TJ, Kontos CD, Cha EH, Prieto VG, Shea CR, Berg JN, Nevin NC, Simpson SA, Pasyk KA, Speer MC, Peters KG, Marchuk DA. Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet. 1999 Jul;8(7):1279-89. PMID:10369874
  5. ↑ Wouters V, Limaye N, Uebelhoer M, Irrthum A, Boon LM, Mulliken JB, Enjolras O, Baselga E, Berg J, Dompmartin A, Ivarsson SA, Kangesu L, Lacassie Y, Murphy J, Teebi AS, Penington A, Rieu P, Vikkula M. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Eur J Hum Genet. 2010 Apr;18(4):414-20. doi: 10.1038/ejhg.2009.193. Epub 2009 Nov, 4. PMID:19888299 doi:10.1038/ejhg.2009.193
  6. ↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
  7. ↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
  8. ↑ Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997 Jul 4;277(5322):55-60. PMID:9204896
  9. ↑ Cascone I, Audero E, Giraudo E, Napione L, Maniero F, Philips MR, Collard JG, Serini G, Bussolino F. Tie-2-dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1. Blood. 2003 Oct 1;102(7):2482-90. Epub 2003 Jun 19. PMID:12816861 doi:10.1182/blood-2003-03-0670
  10. ↑ Lee HJ, Cho CH, Hwang SJ, Choi HH, Kim KT, Ahn SY, Kim JH, Oh JL, Lee GM, Koh GY. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 2004 Aug;18(11):1200-8. PMID:15284220 doi:10.1096/fj.03-1466com
  11. ↑ Audero E, Cascone I, Maniero F, Napione L, Arese M, Lanfrancone L, Bussolino F. Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells. J Biol Chem. 2004 Mar 26;279(13):13224-33. Epub 2003 Dec 9. PMID:14665640 doi:10.1074/jbc.M307456200
  12. ↑ Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 2005 Apr 25;169(2):239-43. PMID:15851516 doi:10.1083/jcb.200411105
  13. ↑ Fukuhara S, Sako K, Minami T, Noda K, Kim HZ, Kodama T, Shibuya M, Takakura N, Koh GY, Mochizuki N. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol. 2008 May;10(5):513-26. doi: 10.1038/ncb1714. Epub 2008 Apr 20. PMID:18425120 doi:10.1038/ncb1714
  14. ↑ Saharinen P, Eklund L, Miettinen J, Wirkkala R, Anisimov A, Winderlich M, Nottebaum A, Vestweber D, Deutsch U, Koh GY, Olsen BR, Alitalo K. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008 May;10(5):527-37. doi: 10.1038/ncb1715. Epub 2008 Apr 20. PMID:18425119 doi:10.1038/ncb1715
  15. ↑ Yuan HT, Khankin EV, Karumanchi SA, Parikh SM. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009 Apr;29(8):2011-22. doi: 10.1128/MCB.01472-08. Epub 2009 Feb, 17. PMID:19223473 doi:10.1128/MCB.01472-08
  16. ↑ Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol. 2008 Jun;23(6):773-80. PMID:18366015
  17. ↑ Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer. 2010 Aug;10(8):575-85. doi: 10.1038/nrc2894. PMID:20651738 doi:10.1038/nrc2894
  18. ↑ Barton WA, Tzvetkova-Robev D, Miranda EP, Kolev MV, Rajashankar KR, Himanen JP, Nikolov DB. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat Struct Mol Biol. 2006 Jun;13(6):524-32. Epub 2006 May 28. PMID:16732286 doi:10.1038/nsmb1101

2gy7, resolution 3.70Å

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