The Role of SmXXXSm Motifs in Wild-Type and Ala391Glu FGFR3 Transmembrane Domain Dimerization

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a single pass membrane protein and a member of the receptor tyrosine kinase (RTK) family of proteins. FGFR3 is critically involved in cellular processes that regulate skeletal growth and development. FGFR3 has three distinct domains: the ligand binding extracellular domain, the cytosolic kinase domain, and the transmembrane domain (TMD). Previous work with the isolated FGFR3 transmembrane (TM) domain has shown that it has the ability to self-dimerize. Mutations in FGFR3 can lead to a variety of diseases, but more specifically, mutations in the TMD of the protein can cause achondroplasia (the most common form of dwarfism, thanatophoric (skeletal) dysplasia, Crouzon syndrome (cranial dysplasia) with acanthosis nigricans (hyperpigmentation of the skin), and bladder cancer. Though the structures of the extracellular and cytosolic domains of FGFR3 have been resolved, the structure of the TMD dimer and the effects of pathogenic mutations on the dimer structure are still unknown. Using the ToxR assay, structural studies were carried out by studying the role of the SmXXXSm motif in the dimerization of the FGFR3 TMD. The SmXXXSm motif has been shown to drive the dimerization of many transmembrane proteins. Results from the ToxR assay indicate that the SmXXXSm does not play a role in the dimerization of the WT FGFR3 TMD. In contrast, similar studies carried out with the A391E mutant TMD show that the SmXXXSm motif plays a role in TMD dimerization. These results lead to the conclusion that the pathogenic A391E TMD has a different dimer structure than the WT FGFR3 TMD.