Structural basis for angiopoietin-1-mediated signaling initiation Journal Article
| Authors: | Yu, X.; Seegar, T. C. M.; Dalton, A. C.; Tzvetkova Robev, D.; Goldgur, Y.; Rajashankar, K. R.; Nikolov, D. B.; Barton, W. A. |
| Article Title: | Structural basis for angiopoietin-1-mediated signaling initiation |
| 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. |
| Keywords: | signal transduction; protein expression; human cell; enzyme activation; cell strain hek293; crystal structure; protein structure; crystallization; angiopoietin receptor; mutagenesis; receptor binding; angiopoietin 2; cellular signaling; x-ray crystallography; angiopoietin 1; cell manipulation; tie receptor tyrosine kinase |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 110 |
| Issue: | 18 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2013-04-30 |
| Start Page: | 7205 |
| End Page: | 7210 |
| Language: | English |
| DOI: | 10.1073/pnas.1216890110 |
| PROVIDER: | scopus |
| PMCID: | PMC3645508 |
| PUBMED: | 23592718 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 June 2013" - "CODEN: PNASA" - "Source: Scopus" |
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