The extracellular domain of fibroblast growth factor receptor 3 inhibits ligand-independent dimerization

Dysregulation of the ligand-independent dimerization of receptor tyrosine kinases (RTKs), which is the first step in the activation of RTKs, leads to various pathologies. A mechanistic understanding of the dimerization process is lacking, and this lack of basic knowledge is one bottleneck in the development of effective RTK-targeted therapies. For example, the roles and relative contributions of the different domains of RTKs to receptor dimerization are unknown. Here, we used quantitative imaging Förster resonance energy transfer (QI-FRET) to determine the contribution of the extracellular domain of fibroblast growth factor receptor 3 (FGFR3) to the dimerization of the receptor. We provide evidence that the contribution of the extracellular domain of FGFR3 to dimerization is repulsive in the absence of ligand and is on the order of ~1 kcal/mol. The repulsive contribution of the extracellular domain is similar in magnitude, but opposite in sign, to the contribution of pathogenic single-amino acid mutations to RTK signaling, and is therefore likely to be important for biological function. Together, these results highlight the fine balance in the domain interactions that regulate RTK dimerization and signaling.