biostudies-literatureUnknownZhao YTNIDCR NIH HHSNCATS NIH HHSNHLBI NIH HHSNIGMS NIH HHSAngiopoietin 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 effects ^1-4 . 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 phenotypbioRxiv : the preprint server for biology2020.09.19.304188https://www.ebi.ac.uk/biostudies/studies/S-EPMC7836102biostudies-literatureF-domain valency determines outcome of signaling through the angiopoietin pathway.PMC7836102P01 GM081619T90 DE021984U01 HL099997R01 GM097372U01 HL099993R01 GM083867TL1 TR002318Ruohola-Baker HSomasundaram LXavier IXu CBaker DFallas JAZhao YTSaini SZhou ZSellers DLMathieu JWrenn SCarter LUeda GEhnes DfalseF-domain valency determines outcome of signaling through the angiopoietin pathway.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 effects ^1-4 . 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 phenotyp2020-01-01T00:00:00Z2020 Dec2026-04-07T22:14:54.645Z2021-02-21T04:12:25ZS-EPMC78361023350143210.1101/2020.09.19.304188