Identification of the binding site for Gqα on its effector Bruton's tyrosine kinase

Yong Chao Ma, Xin Yun Huang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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 Gqα 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 Gqα, not inactive GDP-bound Gqα, can bind to Btk. Mutations of Btk that disrupt its ability to bind Gqα also eliminate Btk stimulation by Gqα, 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 Gqα to the TH- SH3 region, thereby disrupting the TH-SH3 intramolecular interaction and activating Btk.

Original languageEnglish (US)
Pages (from-to)12197-12201
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number21
DOIs
StatePublished - Oct 13 1998

Keywords

  • G protein
  • Signal transduction

ASJC Scopus subject areas

  • General

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