A Model for the Signal Initiation Complex Between Arrestin-3 and the Src Family Kinase Fgr

Perez, Ivette; Berndt, Sandra; Agarwal, Rupesh; Castro, Manuel A.; Vishnivetskiy, Sergey A.; Smith, Jeremy C.; Sanders, Charles R.; Gurevich, Vsevolod V.; Iverson, Tina M.

doi:10.1016/j.jmb.2021.167400

A Model for the Signal Initiation Complex Between Arrestin-3 and the Src Family Kinase Fgr

Journal Article · Sat Dec 11 04:00:00 EST 2021 · Journal of Molecular Biology

DOI:https://doi.org/10.1016/j.jmb.2021.167400· OSTI ID:2538510

Perez, Ivette ^[1]; Berndt, Sandra ^[1]; Agarwal, Rupesh ^[2]; Castro, Manuel A. ^[1]; Vishnivetskiy, Sergey A. ^[3]; Smith, Jeremy C. ^[2]; Sanders, Charles R. ^[1]; Gurevich, Vsevolod V. ^[3]; Iverson, Tina M. ^[1]

Vanderbilt University, Nashville, TN (United States); Center for Structural Biology, Nashville, TN (United States)
University of Tennessee, Knoxville, TN (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Vanderbilt University, Nashville, TN (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE; National Science Foundation (NSF); National Institutes of Health (NIH)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2538510

Journal Information:: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 2 Vol. 434; ISSN 0022-2836

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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