The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition

Juliya Kalinina, Kaushik Dutta, Dariush Ilghari, Andrew Beenken, Regina Goetz, Anna V. Eliseenkova, David Cowburn, Moosa Mohammadi

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)77-88
Number of pages12
JournalStructure
Volume20
Issue number1
DOIs
StatePublished - Jan 11 2012

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Fibroblast Growth Factor Receptors
Acids
Heparitin Sulfate
Fibroblast Growth Factors
Binding Sites
Ligands
Surface Plasmon Resonance
Static Electricity
Amino Acid Sequence
Spectrum Analysis
Magnetic Resonance Spectroscopy
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Kalinina, J., Dutta, K., Ilghari, D., Beenken, A., Goetz, R., Eliseenkova, A. V., ... Mohammadi, M. (2012). The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. Structure, 20(1), 77-88. https://doi.org/10.1016/j.str.2011.10.022

The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. / Kalinina, Juliya; Dutta, Kaushik; Ilghari, Dariush; Beenken, Andrew; Goetz, Regina; Eliseenkova, Anna V.; Cowburn, David; Mohammadi, Moosa.

In: Structure, Vol. 20, No. 1, 11.01.2012, p. 77-88.

Research output: Contribution to journalArticle

Kalinina, J, Dutta, K, Ilghari, D, Beenken, A, Goetz, R, Eliseenkova, AV, Cowburn, D & Mohammadi, M 2012, 'The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition', Structure, vol. 20, no. 1, pp. 77-88. https://doi.org/10.1016/j.str.2011.10.022
Kalinina J, Dutta K, Ilghari D, Beenken A, Goetz R, Eliseenkova AV et al. The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. Structure. 2012 Jan 11;20(1):77-88. https://doi.org/10.1016/j.str.2011.10.022
Kalinina, Juliya ; Dutta, Kaushik ; Ilghari, Dariush ; Beenken, Andrew ; Goetz, Regina ; Eliseenkova, Anna V. ; Cowburn, David ; Mohammadi, Moosa. / The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition. In: Structure. 2012 ; Vol. 20, No. 1. pp. 77-88.
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