Molecular Dynamics Simulations of the Transmembrane Helix of the FGFR3 Receptor in POPC and DPPC

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that negatively regulates bone growth. Elevated FGFR3 activity results in achondroplasia, the most common form of human dwarfism. In the majority (∼98%) of cases the underlying mutation is G380R in the FGFR3 transmembrane domain. We have used coarse-grained molecular dynamics simulations to study the dimerization behaviour of wild-type, heterodimer, and mutant homodimer 33-residue transmembrane FGFR3 constructs in both POPC and DPPC bilayers. FGFR3 dimers are stable once formed in POPC, but dissociations are observed in DPPC. All three FGFR3 constructs exhibit bimodal helix crossing angle distributions, in contrast to the strong preference for right-handed crossing in glycophorin A (GpA) control simulations. We present evidence for a primary FGFR3 dimer interface and a less stable secondary interface. The latter is more pronounced for mutant than wild-type constructs in POPC, but not in DPPC. The helix crossing angle is right-handed at the secondary dimer interface for both heterodimer and mutant homodimer FGFR3 constructs in POPC. G370, A374, and R397 are prevalent FGFR3 dimer contacts, while the same analysis procedure on GpA control simulations selects the most important interfacial residues established by experiment. We suggest subtle differences, relative to wild-type, in the dimerization properties of G380R FGFR3 transmembrane domains.