title: Autoinhibitory mechanism for the mutation-induced impaired FGF9 signaling.
abstract: Fibroblast growth factor 9 (FGF9), an important member of the fibroblast growth factor (FGF) family, can bind with high affinity to FGFR3 in a heparin-dependent approach. In humans, the deletions and mutations resulting in dysfunction of the FGF9 signaling can cause human skeletal dysplasia and cancers. A mutation (S99N) in this protein has been identified to be associated with significantly impaired FGF signaling considered as a potential cause of synostoses syndrome. However, the detailed mechanism for this observation still remains unknown. In this study, we used molecular dynamics simulations and free energy calculations to study the interactions of FGF9(WT/S99N), FGFR3c, and heparin, with an aim of providing atomic sights into the detailed mechanism for the impaired FGF signaling caused by the S99N mutation. We found that the S99N mutation has a well-ordered C-terminal structure, which can reduce its homodimerization ability so as to break the monomer-dimer equilibrium in the FGF signaling, which is considered as a key factor to regulate extracellular matrix affinity and tissue diffusion in the FGF signaling pathway. The FGF9(WT) monomer can preferentially form a homodimer owing to its comparatively favorable binding free energy. In contrast, the FGF9(S99N) monomer is preferred to bind with the FGFR3c receptor to form an inactive complex, leading to impair FGF signaling. To support our computational findings, we also performed biochemical experiments, which confirm the computational results mentioned above. The impaired FGF signaling is believed to be a potential cause of human synostoses syndrome, implicating an important role for FGF9 in normal joint development.
authors.affiliation: Key Laboratory of Systems Biomedicine-Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Wu
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Wei
authors.forename: Yi-Xue
authors.initials: YX
authors.lastname: Li
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Wang
mesh_terms: D051525:Fibroblast Growth Factor 9 / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D015398:Signal Transduction
chemical_list: C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9