Neutron Diffraction Studies of Fluid Bilayers with Transmembrane Proteins: Structural Consequences of the Achondroplasia Mutation

Achondroplasia, the most common form of human dwarfism, is due to a G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) in >97% of the studied cases. While the molecular mechanism of pathology induction is under debate, the structural consequences of the muta...

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Bibliographic Details
Published in:Biophysical journal 2006-11, Vol.91 (10), p.3736-3747
Main Authors: Han, Xue, Mihailescu, Mihaela, Hristova, Kalina
Format: Article
Language:English
Subjects:
Achondroplasia - metabolism
Amino Acid Substitution
Diffraction
Dwarfism
Fluid dynamics
Humans
Lipid Bilayers - chemistry
Membrane Proteins - chemistry
Membranes
Mutation
Neutron Diffraction
Neutrons
Protein Conformation
Proteins
Receptor, Fibroblast Growth Factor, Type 3 - chemistry
Structure-Activity Relationship
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Summary:Achondroplasia, the most common form of human dwarfism, is due to a G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) in >97% of the studied cases. While the molecular mechanism of pathology induction is under debate, the structural consequences of the mutation have not been studied. Here we use neutron diffraction to determine the disposition of FGFR3 transmembrane domain in fluid lipid bilayers, and investigate whether the G380R mutation affects the topology of the protein in the bilayer. Our results demonstrate that, in a model system, the G380R mutation induces a shift in the segment that is embedded in the membrane. The center of the hydrocarbon core-embedded segment in the mutant is close to the midpoint between R380 and R397, supporting previous measurements of arginine insertion energetics into the endoplasmic reticulum. The presented results further our knowledge about basic amino-acid insertion into bilayers, and may lead to new insights into the mechanism of pathogenesis in achondroplasia.
ISSN:0006-3495
1542-0086
DOI:10.1529/biophysj.106.092247