A Model for the Signal Initiation Complex Between Arrestin-3 and the Src Family Kinase Fgr. Issue 2 (30th January 2022)

• Record Type: Journal Article
• Authors: Perez, Ivette; Berndt, Sandra; Agarwal, Rupesh; Castro, Manuel A.; Vishnivetskiy, Sergey A.; Smith, Jeremy C.; Sanders, Charles R.; Gurevich, Vsevolod V.; Iverson, T.M.
• Is Part Of: Journal of molecular biology. Volume 434:Issue 2(2022)
• Publication Date: 2022-01-30
• Subjects: arrestin -- Fgr -- signal initiation complex; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167400
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Arrestins scaffold Fgr in a signal initiation complex. A polyproline sequence in the aSwI region of arrestin-3 binds the Fgr SH3 domain. Assays with arrestin-3 variants support this interaction in cells. Patient mutations of the Fgr SH3 domain suggest this interaction occurs in humans. A model of the signal initiation complex suggests a likely interaction mode. Abstract: Arrestins regulate a wide range of signaling events, most notably when bound to active G protein-coupled receptors (GPCRs). Among the known effectors recruited by GPCR-bound arrestins are Src family kinases, which regulate cellular growth and proliferation. Here, we focus on arrestin-3 interactions with Fgr kinase, a member of the Src family. Previous reports demonstrated that Fgr exhibits high constitutive activity, but can be further activated by both arrestin-dependent and arrestin-independent pathways. We report that arrestin-3 modulates Fgr activity with a hallmark bell-shaped concentration-dependence, consistent with a role as a signaling scaffold. We further demonstrate using NMR spectroscopy that a polyproline motif within arrestin-3 interacts directly with the SH3 domain of Fgr. To provide a framework for this interaction, we determined the crystal structure of the Fgr SH3 domain at 1.9 Å resolution and developed a model for the GPCR-arrestin-3-Fgr complex that is supported by mutagenesis. This model suggests that Fgr interacts with arrestin-3 at multiple sites and is consistent with the locations of disease-associated Fgr mutations. Collectively, these studies provide a structural framework for arrestin-dependent activation of Fgr.