5N06

Crystal structure of Tie1 Fibronectin-like domain 3

Summary for 5N06

• Entry DOI: 10.2210/pdb5n06/pdb
• Descriptor: Tyrosine-protein kinase receptor Tie-1 (2 entities in total)
• Functional Keywords: receptor, fibronectin-like domains, heterodimerization, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P35590
• Total number of polymer chains: 2
• Total formula weight: 28133.81

Authors

Leppanen, V.-M.,Saharinen, P.,Alitalo, K. (deposition date: 2017-02-02, release date: 2017-04-26, Last modification date: 2024-05-01)

Primary citation

Leppanen, V.M.,Saharinen, P.,Alitalo, K.
Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization.
Proc. Natl. Acad. Sci. U.S.A., 114:4376-4381, 2017

PubMed Abstract: 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 and across EC-EC junctions in 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 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 β-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.

PubMed: 28396439
DOI: 10.1073/pnas.1616166114

Experimental method

X-RAY DIFFRACTION (2.501 Å)