Structural basis for angiopoietin-1-mediated signaling initiation

Xuehong Yu, Tom C.M. Seegar, Annamarie C. Dalton, Dorothea Tzvetkova-Robev, Yehuda Goldgur, Kanagalaghatta R. Rajashankar, Dimitar B. Nikolov, William A. Barton

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)7205-7210
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number18
DOIs
StatePublished - 30 Apr 2013
Externally publishedYes

Keywords

  • Cellular signaling
  • Tie receptor tyrosine kinase
  • X-ray crystallography

ASJC Scopus subject areas

  • General

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