Geometric Tuning of Cytokine Receptor Association Modulates Synthetic Agonist Signaling.

ABSTRACT: Cytokines signal by bringing receptor subunits together, but the role of receptor geometry in shaping signaling remains unclear because natural ligands enforce fixed assemblies. Here, we present a de novo protein design platform that rigidly scaffolds receptor-binding domains into defined spatial arrangements. Applying this across IL-7, type I and III interferons, IL-10, gp130, β common, and synthetic receptor pairs, we show that by varying geometry, we can bias pSTAT pathway usage and tune functional outcomes. Geometric control allowed us to decouple pSTAT1 from pSTAT5 in IL-7, separate antigen presentation (MHC-I) from checkpoint induction (PD-L1) in type I interferons, and suppress pro-inflammatory IFNγ secretion while retaining anti-inflammatory activity in IL-10. We further cre

SUBMITTER: Exposit M 

PROVIDER: S-EPMC12632830 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature