EUROMAR 2011, 2011, 191

Structural and dynamical model of transmembrane domain of fibroblast growth factor receptor 3

Homodimerization and dynamic properties of the transmembrane segment of fibroblast growth factor receptor 3, participating in signal transduction through the cell membrane, were characterized by heteronuclear NMR spectroscopy in the membrane-mimicking environment. The helix-helix dimerization heptad motif (YA374X2L377X2G380X2FF384X2IL388X2A391X2TL395) is employed for a left-handed parallel packing with crossing angle of ~20o and helix-helix distance of ~9 Å. The central region of the dimer is characterized by relatively tight packing stabilized by intra- and intermolecular stacking interactions of aromatic rings (Y379–FF384–F386), whereas N-terminal part of transmembrane helix is stabilized upon dimer formation that can be related with the receptor activation. The pathogenic mutations Y373C, G380R and A391E are located precisely in the in the helix-helix interface assuming that the obtained dimer conformation is important for receptor functioning. The NMR results combined with molecular modeling data providing detailed analysis of conformational space as well as influence of mutations on structure, stability and dynamic properties of the dimer.

IBCH: 6869
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