TY - JOUR
T1 - Mechanism of FGF receptor dimerization and activation
AU - Sarabipour, Sarvenaz
AU - Hristova, Kalina
N1 - Funding Information:
This work was supported by NIH GM68619, GM95930 and NSF MCB1157687. We thank Dr D. J. Donoghue for the full-length FGFR3 plasmid, and Dr Moosa Mohammadi for the full-length FGFR1 and FGFR2 plasmids. We are grateful to Drs Michael Edidin, Daniel Leahy, William C. Wimley, Eduard Bocharov and Pavel Krejci for critical reading of the manuscript prior to publication, and for insightful comments. We thank Christopher King for help with data analysis and Anna Frishman for help with cloning.
PY - 2016/1/4
Y1 - 2016/1/4
N2 - Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. Here we show, however, that the FGF receptors form dimers in the absence of ligand, and that these unliganded dimers are phosphorylated. We further show that ligand binding triggers structural changes in the FGFR dimers, which increase FGFR phosphorylation. The observed effects due to the ligands fgf1 and fgf2 are very different. The fgf2-bound dimer structure ensures the smallest separation between the transmembrane (TM) domains and the highest possible phosphorylation, a conclusion that is supported by a strong correlation between TM helix separation in the dimer and kinase phosphorylation. The pathogenic A391E mutation in FGFR3 TM domain emulates the action of fgf2, trapping the FGFR3 dimer in its most active state. This study establishes the existence of multiple active ligand-bound states, and uncovers a novel molecular mechanism through which FGFR-linked pathologies can arise.
AB - Fibroblast growth factors (fgfs) are widely believed to activate their receptors by mediating receptor dimerization. Here we show, however, that the FGF receptors form dimers in the absence of ligand, and that these unliganded dimers are phosphorylated. We further show that ligand binding triggers structural changes in the FGFR dimers, which increase FGFR phosphorylation. The observed effects due to the ligands fgf1 and fgf2 are very different. The fgf2-bound dimer structure ensures the smallest separation between the transmembrane (TM) domains and the highest possible phosphorylation, a conclusion that is supported by a strong correlation between TM helix separation in the dimer and kinase phosphorylation. The pathogenic A391E mutation in FGFR3 TM domain emulates the action of fgf2, trapping the FGFR3 dimer in its most active state. This study establishes the existence of multiple active ligand-bound states, and uncovers a novel molecular mechanism through which FGFR-linked pathologies can arise.
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U2 - 10.1038/ncomms10262
DO - 10.1038/ncomms10262
M3 - Article
C2 - 26725515
AN - SCOPUS:84953331204
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 10262
ER -