TY - JOUR
T1 - FGFR3 dimer stabilization due to a single amino acid pathogenic mutation
AU - Li, Edwin
AU - You, Min
AU - Hristova, Kalina
N1 - Funding Information:
We thank Jamie Spangler and Xue Han for peptide synthesis. We are grateful to Dr Paul Adams for providing us with the CHI software, and to Dr Tihomir Hristov and Anastasia Gentilcore for assistance with structure modeling. We thank Drs Daniel Donoghue, Michael Edidin, James Bowie, William C. Wimley, Michael Wiener, Clair Francomano, Jay Gargus, and Ethylin Jabs for stimulating discussions. This work was supported by Research Scholar Grant # RSG-04-201-01 from the American Cancer Society to K.H.
PY - 2006/2/24
Y1 - 2006/2/24
N2 - Mutations in the transmembrane (TM) domains of receptor tyrosine kinases (RTKs) have been implicated in the induction of pathological phenotypes. These mutations are believed to stabilize the RTK dimers, and thus promote unregulated signaling. However, the energetics behind the pathology induction has not been determined. An example of a TM domain pathogenic mutation is the Ala391→Glu mutation in fibroblast growth factor receptor 3 (FGFR3), linked to Crouzon syndrome with acanthosis nigricans, as well as to bladder cancer. Here, we determine the free energy of dimerization of wild-type and mutant FGFR3 TM domain in lipid bilayers using Förster resonance energy transfer, and we show that hydrogen bonding between Glu391 and the adjacent helix in the dimer is a feasible mechanism for dimer stabilization. The measured change in the free energy of dimerization due to the Ala391→Glu pathogenic mutation is -1.3 kcal/mol, consistent with previous reports of hydrogen bond strengths in proteins. This is the first quantitative measurement of mutant RTK stabilization in a membrane environment. We show that this seemingly modest value can lead to a large increase in dimer fraction and thus profoundly affect RTK-mediated signal transduction.
AB - Mutations in the transmembrane (TM) domains of receptor tyrosine kinases (RTKs) have been implicated in the induction of pathological phenotypes. These mutations are believed to stabilize the RTK dimers, and thus promote unregulated signaling. However, the energetics behind the pathology induction has not been determined. An example of a TM domain pathogenic mutation is the Ala391→Glu mutation in fibroblast growth factor receptor 3 (FGFR3), linked to Crouzon syndrome with acanthosis nigricans, as well as to bladder cancer. Here, we determine the free energy of dimerization of wild-type and mutant FGFR3 TM domain in lipid bilayers using Förster resonance energy transfer, and we show that hydrogen bonding between Glu391 and the adjacent helix in the dimer is a feasible mechanism for dimer stabilization. The measured change in the free energy of dimerization due to the Ala391→Glu pathogenic mutation is -1.3 kcal/mol, consistent with previous reports of hydrogen bond strengths in proteins. This is the first quantitative measurement of mutant RTK stabilization in a membrane environment. We show that this seemingly modest value can lead to a large increase in dimer fraction and thus profoundly affect RTK-mediated signal transduction.
KW - Cancer
KW - Fibroblast growth factor receptor 3
KW - Hydrogen bond
KW - Receptor tyrosine kinase
KW - Transmembrane domain
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U2 - 10.1016/j.jmb.2005.11.077
DO - 10.1016/j.jmb.2005.11.077
M3 - Article
C2 - 16384584
AN - SCOPUS:31344468061
SN - 0022-2836
VL - 356
SP - 600
EP - 612
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 3
ER -