5n06
From Proteopedia
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/TIE1_HUMAN TIE1_HUMAN] Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis.<ref>PMID:20227369</ref> | [https://www.uniprot.org/uniprot/TIE1_HUMAN TIE1_HUMAN] Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis.<ref>PMID:20227369</ref> | ||
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| - | == Publication Abstract from PubMed == | ||
| - | The endothelial cell (EC)-specific receptor tyrosine kinases Tie1 and Tie2 are necessary for the remodeling and maturation of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth factor is a Tie2 agonist, whereas Ang2 functions as a context-dependent agonist/antagonist. The orphan receptor Tie1 modulates Tie2 activation, which is induced by association of angiopoietins with Tie2 in cis and across EC-EC junctions in trans Except for the binding of the C-terminal angiopoietin domains to the Tie2 ligand-binding domain, the mechanisms for Tie2 activation are poorly understood. We report here the structural basis of Ang1-induced Tie2 dimerization in cis and provide mechanistic insights on Ang2 antagonism, Tie1/Tie2 heterodimerization, and Tie2 clustering. We find that Ang1-induced Tie2 dimerization and activation occurs via the formation of an intermolecular beta-sheet between the membrane-proximal (third) Fibronectin type III domains (Fn3) of Tie2. The structures of Tie2 and Tie1 Fn3 domains are similar and compatible with Tie2/Tie1 heterodimerization by the same mechanism. Mutagenesis of the key interaction residues of Tie2 and Tie1 Fn3 domains decreased Ang1-induced Tie2 phosphorylation and increased the basal phosphorylation of Tie1, respectively. Furthermore, the Tie2 structures revealed additional interactions between the Fn 2 (Fn2) domains that coincide with a mutation of Tie2 in primary congenital glaucoma that leads to defective Tie2 clustering and junctional localization. Mutagenesis of the Fn2-Fn2 interface increased the basal phosphorylation of Tie2, suggesting that the Fn2 interactions are essential in preformed Tie2 oligomerization. The interactions of the membrane-proximal domains could provide new targets for modulation of Tie receptor activity. | ||
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| - | Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization.,Leppanen VM, Saharinen P, Alitalo K Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4376-4381. doi:, 10.1073/pnas.1616166114. Epub 2017 Apr 10. PMID:28396439<ref>PMID:28396439</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
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| - | <div class="pdbe-citations 5n06" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
Current revision
Crystal structure of Tie1 Fibronectin-like domain 3
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