Identification of the binding site for Gqα on its effector Bruton's tyrosine kinase Article Conference Paper uri icon

Overview

MeSH Major

  • Cell Movement
  • Epidermal Growth Factor
  • GTP-Binding Protein alpha Subunits, G12-G13
  • Platelet-Derived Growth Factor
  • Receptor Protein-Tyrosine Kinases

abstract

  • Heterotrimeric G proteins and tyrosine kinases are two major cellular signal transducers. Although G proteins are known to activate tyrosine kinases, the activation mechanism is not clear. Here, we demonstrate that G protein Gqalpha binds directly to the nonreceptor Bruton's tyrosine kinase (Btk) to a region composed of a Tec-homology (TH) domain and a sarcoma virus tyrosine kinase (Src)-homology 3 (SH3) domain both in vitro and in vivo. Only active GTP-bound Gqalpha, not inactive GDP-bound Gqalpha, can bind to Btk. Mutations of Btk that disrupt its ability to bind Gqalpha also eliminate Btk stimulation by Gqalpha, suggesting that this interaction is important for Btk activation. Remarkably, the structure of this TH (including a proline-rich sequence) -SH3 fragment of the Btk family of tyrosine kinases shows an intramolecular interaction. Furthermore, the crystal structure of the Src family of tyrosine kinases reveals that the intramolecular interaction of SH3 and its ligand is the major determining factor keeping the kinase inactive. Thus, we propose an activation model that entails binding of Gqalpha to the TH-SH3 region, thereby disrupting the TH-SH3 intramolecular interaction and activating Btk.

publication date

  • October 13, 1998

Research

keywords

  • Conference Paper

Identity

Digital Object Identifier (DOI)

  • 10.1073/pnas.95.21.12197

PubMed ID

  • 9770463

Additional Document Info

start page

  • 12197

end page

  • 201

volume

  • 95

number

  • 21