TY - JOUR
T1 - Structure of FGFR3 transmembrane domain dimer
T2 - Implications for signaling and human pathologies
AU - Bocharov, Eduard V.
AU - Lesovoy, Dmitry M.
AU - Goncharuk, Sergey A.
AU - Goncharuk, Marina V.
AU - Hristova, Kalina
AU - Arseniev, Alexander S.
N1 - Funding Information:
The authors express their sincere thanks to Drs. P.E. Volynsky and K.V. Pavlov for helpful discussions. This work was supported by the Russian Academy of Sciences Program “Molecular and Cellular Biology,” Russian Foundation for Basic Research (12-04-01816-a and 14-04-31947 mol_a) and National Institutes of Health (GM068619) grants. E.V.B. personally thanks K.A. Beirit (“Russian Funds” Investment Group) for financial support.
PY - 2013/11/5
Y1 - 2013/11/5
N2 - Fibroblast growth factor receptor 3 (FGFR3) transduces biochemical signals via lateral dimerization in the plasma membrane, and plays an important role in human development and disease. Eight different pathogenic mutations, implicated in cancers and growth disorders, have been identified in the FGFR3 transmembrane segment. Here, we describe the dimerization of the FGFR3 transmembrane domain in membrane-mimicking DPC/SDS (9/1) micelles. In the solved NMR structure, the two transmembrane helices pack into a symmetric left-handed dimer, with intermolecular stacking interactions occurring in the dimer central region. Some pathogenic mutations fall within the helix-helix interface, whereas others are located within a putative alternative interface. This implies that although the observed dimer structure is important for FGFR3 signaling, the mechanism of FGFR3-mediated transduction across the membrane is complex. We propose an FGFR3 signaling mechanism that is based on the solved structure, available structures of isolated soluble FGFR domains, and published biochemical and biophysical data.
AB - Fibroblast growth factor receptor 3 (FGFR3) transduces biochemical signals via lateral dimerization in the plasma membrane, and plays an important role in human development and disease. Eight different pathogenic mutations, implicated in cancers and growth disorders, have been identified in the FGFR3 transmembrane segment. Here, we describe the dimerization of the FGFR3 transmembrane domain in membrane-mimicking DPC/SDS (9/1) micelles. In the solved NMR structure, the two transmembrane helices pack into a symmetric left-handed dimer, with intermolecular stacking interactions occurring in the dimer central region. Some pathogenic mutations fall within the helix-helix interface, whereas others are located within a putative alternative interface. This implies that although the observed dimer structure is important for FGFR3 signaling, the mechanism of FGFR3-mediated transduction across the membrane is complex. We propose an FGFR3 signaling mechanism that is based on the solved structure, available structures of isolated soluble FGFR domains, and published biochemical and biophysical data.
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U2 - 10.1016/j.str.2013.08.026
DO - 10.1016/j.str.2013.08.026
M3 - Article
C2 - 24120763
AN - SCOPUS:84887406746
SN - 0969-2126
VL - 21
SP - 2087
EP - 2093
JO - Structure
JF - Structure
IS - 11
ER -