Structural basis for angiopoietin-1–mediated signaling initiation
- Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
- Virginia Commonwealth Univ., Richmond, VA (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- UNIVERSITYNIHOTHER
- OSTI ID:
- 1082512
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, Issue 18; ISSN 0027-8424
- Publisher:
- National Academy of Sciences, Washington, DC (United States)
- Country of Publication:
- United States
- Language:
- ENGLISH
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