The strong dimerization of the transmembrane domain of the fibroblast growth factor receptor (FGFR) is modulated by C-terminal juxtamembrane residues.
The fibroblast growth factor receptor 3 (FGFR3) is a member of the FGFR subfamily of the receptor tyrosine kinases (RTKs) involved in signaling across the plasma membrane. Generally, ligand binding leads to receptor dimerization and activation. Dimerization involves the transmembrane (TM) domain, where mutations can lead to constitutive activation in certain cancer types and also in skeletal malformations. Thus, it has been postulated that FGFR homodimerization must be inherently weak to allow regulation, a feature reminiscent of alpha and beta integrin TM interactions. However, we show herein that in FGFR3-TM, four C-terminal residues, CRLR, have a profound destabilizing effect in an otherwise strongly dimerizing TM peptide. In the absence of these four residues, the dimerizing propensity of FGFR3-TM is comparable to glycophorin, as shown using various detergents. In addition, the expected enhanced dimerization induced by the mutation associated to the Crouzon syndrome A391E, was observed only when these four C-terminal residues were present. In the absence of these four residues, A391E was dimer-destabilizing. Finally, using site specific infrared dichroism and convergence with evolutionary conservation data, we have determined the backbone model of the FGFR3-TM homodimer in model lipid bilayers. This model is consistent with, and correlates with the effects of, most known pathological mutations found in FGFR-TM.
Peng
Weng Chuan
WC
Nanyang Technological University, Singapore.
Lin
Xin
X
Torres
Jaume
J
D000595:Amino Acid Sequence; D000818:Animals; D002247:Carbon Isotopes / Q000737:chemistry; D002942:Circular Dichroism; D016000:Cluster Analysis; D003198:Computer Simulation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007553:Isotope Labeling; D008051:Lipid Bilayers; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010103:Oxygen Isotopes / Q000737:chemistry; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D055503:Protein Multimerization; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment; D017550:Spectroscopy, Fourier Transform Infrared
D002247:Carbon Isotopes; D008051:Lipid Bilayers; D010103:Oxygen Isotopes; D010446:Peptide Fragments; D017468:Receptors, Fibroblast Growth Factor