A de novo-designed mini-protein can inhibit FGFR signaling in an isoform-specific manner.

Abstract

Fibroblast growth factors (FGFs) are a family of proteins that regulate critical physiological functions such as growth, development, and metabolism, which function by binding to and signaling through fibroblast growth factor receptors (FGFRs), a group of cell surface receptors that belong to receptor tyrosine kinase (RTK) superfamily. Cellular signaling by FGFRs is a highly regulated process mediated by specific interactions between distinct subsets of FGF ligands and two FGFR isoforms generated by alternative splicing: epithelial b- and mesenchymal c-isoforms. Here we show that a de novo-designed mini-protein, mb7, can specifically bind to the c-isoforms of FGFR with high-affinity resulting in inhibition of cellular signaling induced by FGFs that preferentially activate c-isoforms of FGFR. Notably, as mb7 blocks interaction between FGFR with Klotho proteins it functions as an antagonist of the metabolic hormones FGF19 and FGF21 providing mechanistic insights and strategies for the development of therapeutics for diseases driven by aberrantly activated FGFRs.