Web Release Date: April 6,
The Achondroplasia Mutation Does Not Alter the Dimerization Energetics of the
Fibroblast Growth Factor Receptor 3 Transmembrane Domain
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218
Received January 18, 2006
Revised Manuscript Received March 8, 2006
Abstract:
The Gly380 
Arg mutation in the TM domain of fibroblast growth factor receptor 3 (FGFR3)
of the RTK family is linked to achondroplasia, the most common form of human dwarfism. The molecular
mechanism of pathology induction is under debate, and two different mechanisms have been proposed to
contribute to pathogenesis: (1) Arg380-mediated FGFR3 dimer stabilization and (2) slow downregulation
of the activated mutant receptors. Here we show that the Gly380 Arg mutation does not alter the
dimerization energetics of the FGFR3 transmembrane domain in detergent micelles or in lipid bilayers.
This result indicates that pathogenesis in achondroplasia cannot be explained simply by a higher dimerization
propensity of the mutant FGFR3 TM domain, thus highlighting the importance of the observed slow
downregulation in phenotype induction.
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