title: The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition.
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.
authors.affiliation: Department of Pharmacology, New York University School of Medicine, 550, First Avenue, New York, NY 10016, USA.
authors.forename: Juliya
authors.initials: J
authors.lastname: Kalinina
authors.forename: Kaushik
authors.initials: K
authors.lastname: Dutta
authors.forename: Dariush
authors.initials: D
authors.lastname: Ilghari
authors.forename: Andrew
authors.initials: A
authors.lastname: Beenken
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.forename: Anna V
authors.initials: AV
authors.lastname: Eliseenkova
authors.forename: David
authors.initials: D
authors.lastname: Cowburn
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D055672:Static Electricity; D020349:Surface Plasmon Resonance
chemical_list: D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D017468:Receptors, Fibroblast Growth Factor