PT  - JOURNAL ARTICLE
AU  - Yan Ting Zhao
AU  - Jorge A. Fallas
AU  - Shally Saini
AU  - George Ueda
AU  - Logeshwaran Somasundaram
AU  - Ziben Zhou
AU  - Infencia Xavier
AU  - Devon Ehnes
AU  - Chunfu Xu
AU  - Lauren Carter
AU  - Samuel Wrenn
AU  - Julie Mathieu
AU  - Drew L. Sellers
AU  - David Baker
AU  - Hannele Ruohola-Baker
TI  - F-domain valency determines outcome of signaling through the angiopoietin pathway
AID  - 10.1101/2020.09.19.304188
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.19.304188
4099  - http://biorxiv.org/content/early/2020/12/24/2020.09.19.304188.short
4100  - http://biorxiv.org/content/early/2020/12/24/2020.09.19.304188.full
AB  - Angiopoietin 1 and 2 (Ang1 and Ang2) modulate angiogenesis and vascular homeostasis through engagement of their very similar F-domain modules with the Tie2 receptor tyrosine kinase on endothelial cells. Despite this similarity in the underlying receptor binding interaction, the two angiopoietins have opposite effects: Ang1 induces phosphorylation of protein kinase B (AKT), strengthens cell-cell junctions and enhances endothelial cell survival while Ang2 antagonizes these effects1–4. To investigate the molecular basis for the opposing effects, we examined the protein kinase activation and morphological phenotypes produced by a series of computationally designed protein scaffolds presenting the Ang1 F-domain in a wide range of valencies and geometries. We find two broad phenotypic classes distinguished by the number of presented F-domains: scaffolds presenting 4 F-domains have Ang2 like activity, upregulating pFAK and pERK but not pAKT, and failing to induce cell migration and tube formation, while scaffolds presenting 6 or more F-domains have Ang1 like activity, upregulating pAKT and inducing migration and tube formation. The scaffolds with 8 or more F-domains display superagonist activity, producing stronger phenotypes at lower concentrations than Ang1. When examined in vivo, superagonist icosahedral self-assembling nanoparticles caused significant revascularization in hemorrhagic brains after a controlled cortical impact injury.Competing Interest StatementThe authors have declared no competing interest.