Neutron diffraction studies of fluid bilayers with transmembrane proteins: structural consequences of the achondroplasia mutation.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleNeutron diffraction studies of fluid bilayers with transmembrane proteins: structural consequences of the achondroplasia mutation.
Publication TypeJournal Article
Year of Publication2006
AuthorsHan, X, Mihailescu, M, Hristova, K
JournalBiophys J
Volume91
Issue10
Pagination3736-47
Date Published2006 Nov 15
ISSN0006-3495
KeywordsAchondroplasia, Amino Acid Substitution, Humans, Lipid Bilayers, Membrane Proteins, Mutation, Neutron Diffraction, Protein Conformation, Receptor, Fibroblast Growth Factor, Type 3, Structure-Activity Relationship
Abstract

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.

DOI10.1529/biophysj.106.092247
Alternate JournalBiophys. J.
PubMed ID16950849
PubMed Central IDPMC1630470
Grant ListGM 068619 / GM / NIGMS NIH HHS / United States
RR1481-2 / RR / NCRR NIH HHS / United States