title: Primary and secondary dimer interfaces of the fibroblast growth factor receptor 3 transmembrane domain: characterization via multiscale molecular dynamics simulations.
abstract: Receptor tyrosine kinases are single-pass membrane proteins that form dimers within the membrane. The interactions of their transmembrane domains (TMDs) play a key role in dimerization and signaling. Fibroblast growth factor receptor 3 (FGFR3) is of interest as a G380R mutation in its TMD is the underlying cause of ~99% of the cases of achondroplasia, the most common form of human dwarfism. The structural consequences of this mutation remain uncertain: the mutation shifts the position of the TMD relative to the lipid bilayer but does not alter the association free energy. We have combined coarse-grained and all-atom molecular dynamics simulations to study the dimerization of wild-type, heterodimer, and mutant FGFR3 TMDs. The simulations reveal that the helices pack together in the dimer to form a flexible interface. The primary packing mode is mediated by a Gx3G motif. There is also a secondary dimer interface that is more highly populated in heterodimer and mutant configurations that may feature in the molecular mechanism of pathology. Both coarse-grained and atomistic simulations reveal a significant shift of the G380R mutant dimer TMD relative to the bilayer to allow interactions of the arginine side chain with lipid headgroup phosphates.
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Tyler
authors.initials: T
authors.lastname: Reddy
authors.forename: Santiago
authors.initials: S
authors.lastname: Manrique
authors.forename: Amanda
authors.initials: A
authors.lastname: Buyan
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hall
authors.forename: Alan
authors.initials: A
authors.lastname: Chetwynd
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D051498:Receptor, Fibroblast Growth Factor, Type 3