5n06

From Proteopedia

Crystal structure of Tie1 Fibronectin-like domain 3

PDB ID 5n06

Drag the structure with the mouse to rotate

Structural highlights

5n06 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 2.501Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TIE1_HUMAN Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis.^[1]

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.

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^[2]

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

References

↑ Seegar TC, Eller B, Tzvetkova-Robev D, Kolev MV, Henderson SC, Nikolov DB, Barton WA. Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands. Mol Cell. 2010 Mar 12;37(5):643-55. doi: 10.1016/j.molcel.2010.02.007. PMID:20227369 doi:http://dx.doi.org/10.1016/j.molcel.2010.02.007
↑ Leppanen VM, Saharinen P, Alitalo K. Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. 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 doi:http://dx.doi.org/10.1073/pnas.1616166114