Structural basis for angiopoietin-1-mediated signaling initiation.

Publication Type:

Journal Article


Proc Natl Acad Sci U S A, Volume 110, Issue 18, p.7205-10 (2013)


Angiopoietin-1, Angiopoietin-2, Conserved Sequence, Crystallography, X-Ray, HEK293 Cells, Humans, Models, Molecular, Protein Structure, Tertiary, Receptor, TIE-1, Receptor, TIE-2, Recombinant Proteins, Signal Transduction, Static Electricity, Structure-Activity Relationship


<p>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.</p>