7JT9

Fgr SH3 domain crystal structure

Summary for 7JT9

• Entry DOI: 10.2210/pdb7jt9/pdb
• Descriptor: Tyrosine-protein kinase Fgr (2 entities in total)
• Functional Keywords: src family kinase, sh3 domain, oncoprotein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 8151.98

Authors

Perez, I.,Berndt, S.,Gurevich, V.V.,Iverson, T.M. (deposition date: 2020-08-17, release date: 2022-01-26, Last modification date: 2023-10-18)

Primary citation

Perez, I.,Berndt, S.,Agarwal, R.,Castro, M.A.,Vishnivetskiy, S.A.,Smith, J.C.,Sanders, C.R.,Gurevich, V.V.,Iverson, T.M.
A Model for the Signal Initiation Complex Between Arrestin-3 and the Src Family Kinase Fgr.
J.Mol.Biol., 434:167400-167400, 2022

PubMed 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.

PubMed: 34902430
DOI: 10.1016/j.jmb.2021.167400

Experimental method

X-RAY DIFFRACTION (1.93 Å)