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{{STRUCTURE_4jyo|  PDB=4jyo  |  SCENE=  }}
==Structural basis for angiopoietin-1 mediated signaling initiation==
===Structural basis for angiopoietin-1 mediated signaling initiation===
<StructureSection load='4jyo' size='340' side='right' caption='[[4jyo]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
{{ABSTRACT_PUBMED_23592718}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4jyo]] is a 1 chain structure with sequence 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=4JYO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JYO 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></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ANGPT1, KIAA0003 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4jyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jyo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jyo RCSB], [http://www.ebi.ac.uk/pdbsum/4jyo PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Angiogenesis is a complex cellular process involving multiple regulatory growth factors and growth factor receptors. Among them, the ligands for the endothelial-specific tunica intima endothelial receptor tyrosine kinase 2 (Tie2) receptor kinase, angiopoietin-1 (Ang1) and Ang2, play essential roles in balancing vessel stability and regression during both developmental and tumor-induced angiogenesis. Despite possessing a high degree of sequence identity, Ang1 and Ang2 have distinct functional roles and cell-signaling characteristics. Here, we present the crystal structures of Ang1 both unbound and in complex with the Tie2 ectodomain. Comparison of the Ang1-containing structures with their Ang2-containing counterparts provide insight into the mechanism of receptor activation and reveal molecular surfaces important for interactions with Tie2 coreceptors and associated signaling proteins. Using structure-based mutagenesis, we identify a loop within the angiopoietin P domain, adjacent to the receptor-binding interface, which confers the specific agonist/antagonist properties of the molecule. We demonstrate using cell-based assays that an Ang2 chimera containing the Ang1 loop sequence behaves functionally similarly to Ang1 as a constitutive Tie2 agonist, able to efficiently dissociate the inhibitory Tie1/Tie2 complex and elicit Tie2 clustering and downstream signaling.


==Function==
Structural basis for angiopoietin-1-mediated signaling initiation.,Yu X, Seegar TC, Dalton AC, Tzvetkova-Robev D, Goldgur Y, Rajashankar KR, Nikolov DB, Barton WA Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7205-10. doi:, 10.1073/pnas.1216890110. Epub 2013 Apr 16. PMID:23592718<ref>PMID:23592718</ref>
[[http://www.uniprot.org/uniprot/ANGP1_HUMAN ANGP1_HUMAN]] Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation. Plays an important role in the regulation of angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Required for normal angiogenesis and heart development during embryogenesis. 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. Mediates blood vessel maturation/stability. Implicated in endothelial developmental processes later and distinct from that of VEGF. Appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.<ref>PMID:9204896</ref> <ref>PMID:15284220</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4jyo]] is a 1 chain structure with sequence 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=4JYO OCA].
</div>
 
== References ==
==Reference==
<references/>
<references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Barton, W A.]]
[[Category: Barton, W A]]
[[Category: Dalton, A C.]]
[[Category: Dalton, A C]]
[[Category: Goldgur, Y.]]
[[Category: Goldgur, Y]]
[[Category: Nikolov, D B.]]
[[Category: Nikolov, D B]]
[[Category: Seegar, T C.M.]]
[[Category: Seegar, T C.M]]
[[Category: Tzvetkova-Robev, D.]]
[[Category: Tzvetkova-Robev, D]]
[[Category: Yu, X.]]
[[Category: Yu, X]]
[[Category: Cellular signaling]]
[[Category: Cellular signaling]]
[[Category: Signaling protein]]
[[Category: Signaling protein]]
[[Category: Tie receptor tyrosine kinase]]
[[Category: Tie receptor tyrosine kinase]]

Revision as of 17:39, 21 December 2014

Structural basis for angiopoietin-1 mediated signaling initiationStructural basis for angiopoietin-1 mediated signaling initiation

Structural highlights

4jyo is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:ANGPT1, KIAA0003 (Homo sapiens)
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

Angiogenesis is a complex cellular process involving multiple regulatory growth factors and growth factor receptors. Among them, the ligands for the endothelial-specific tunica intima endothelial receptor tyrosine kinase 2 (Tie2) receptor kinase, angiopoietin-1 (Ang1) and Ang2, play essential roles in balancing vessel stability and regression during both developmental and tumor-induced angiogenesis. Despite possessing a high degree of sequence identity, Ang1 and Ang2 have distinct functional roles and cell-signaling characteristics. Here, we present the crystal structures of Ang1 both unbound and in complex with the Tie2 ectodomain. Comparison of the Ang1-containing structures with their Ang2-containing counterparts provide insight into the mechanism of receptor activation and reveal molecular surfaces important for interactions with Tie2 coreceptors and associated signaling proteins. Using structure-based mutagenesis, we identify a loop within the angiopoietin P domain, adjacent to the receptor-binding interface, which confers the specific agonist/antagonist properties of the molecule. We demonstrate using cell-based assays that an Ang2 chimera containing the Ang1 loop sequence behaves functionally similarly to Ang1 as a constitutive Tie2 agonist, able to efficiently dissociate the inhibitory Tie1/Tie2 complex and elicit Tie2 clustering and downstream signaling.

Structural basis for angiopoietin-1-mediated signaling initiation.,Yu X, Seegar TC, Dalton AC, Tzvetkova-Robev D, Goldgur Y, Rajashankar KR, Nikolov DB, Barton WA Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7205-10. doi:, 10.1073/pnas.1216890110. Epub 2013 Apr 16. PMID:23592718[1]

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

References

  1. ↑ Yu X, Seegar TC, Dalton AC, Tzvetkova-Robev D, Goldgur Y, Rajashankar KR, Nikolov DB, Barton WA. Structural basis for angiopoietin-1-mediated signaling initiation. Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7205-10. doi:, 10.1073/pnas.1216890110. Epub 2013 Apr 16. PMID:23592718 doi:http://dx.doi.org/10.1073/pnas.1216890110

4jyo, resolution 2.50Å

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