TY - JOUR
T1 - The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition
AU - Kalinina, Juliya
AU - Dutta, Kaushik
AU - Ilghari, Dariush
AU - Beenken, Andrew
AU - Goetz, Regina
AU - Eliseenkova, Anna V.
AU - Cowburn, David
AU - Mohammadi, Moosa
N1 - Funding Information:
This work was supported by U.S. National Institutes of Health grants DE13686 (M.M.) and GM47021 (D.C.). Support for the Biacore 2000 SPR instrument was provided by grant P30 NS050276. We are grateful to Dr. Michael Goger for helpful discussions of NMR issues and to Jinghong Ma for preparing the structure figure shown in panel A of Figure 1.
PY - 2012/1/11
Y1 - 2012/1/11
N2 - Uncontrolled fibroblast growth factor (FGF) signaling can lead to human malignancies necessitating multiple layers of self-regulatory control mechanisms. Fibroblast growth factor receptor (FGFR) autoinhibition mediated by the alternatively spliced immunoglobulin (Ig) domain 1 (D1) and the acid box (AB)-containing linker between D1 and Ig domain 2 (D2) serves as the first line of defense to minimize inadvertent FGF signaling. In this report, nuclear magnetic resonance and surface plasmon resonance spectroscopy are used to demonstrate that the AB subregion of FGFR electrostatically engages the heparan sulfate (HS)-binding site on the D2 domain in cis to directly suppress HS-binding affinity of FGFR. Furthermore, the cis electrostatic interaction sterically autoinhibits ligand-binding affinity of FGFR because of the close proximity of HS-binding and primary ligand-binding sites on the D2 domain. These data, together with the strong amino acid sequence conservation of the AB subregion among FGFR orthologs, highlight the universal role of the AB subregion in FGFR autoinhibition.
AB - Uncontrolled fibroblast growth factor (FGF) signaling can lead to human malignancies necessitating multiple layers of self-regulatory control mechanisms. Fibroblast growth factor receptor (FGFR) autoinhibition mediated by the alternatively spliced immunoglobulin (Ig) domain 1 (D1) and the acid box (AB)-containing linker between D1 and Ig domain 2 (D2) serves as the first line of defense to minimize inadvertent FGF signaling. In this report, nuclear magnetic resonance and surface plasmon resonance spectroscopy are used to demonstrate that the AB subregion of FGFR electrostatically engages the heparan sulfate (HS)-binding site on the D2 domain in cis to directly suppress HS-binding affinity of FGFR. Furthermore, the cis electrostatic interaction sterically autoinhibits ligand-binding affinity of FGFR because of the close proximity of HS-binding and primary ligand-binding sites on the D2 domain. These data, together with the strong amino acid sequence conservation of the AB subregion among FGFR orthologs, highlight the universal role of the AB subregion in FGFR autoinhibition.
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U2 - 10.1016/j.str.2011.10.022
DO - 10.1016/j.str.2011.10.022
M3 - Article
C2 - 22244757
AN - SCOPUS:84855775666
SN - 0969-2126
VL - 20
SP - 77
EP - 88
JO - Structure
JF - Structure
IS - 1
ER -