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Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP

Qi Hu1, Kevan M Shokat2

  • 1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California-San Francisco, San Francisco, CA 94158, USA.

Cell
|April 10, 2018
PubMed

Insights

Cancer-causing Gαs mutations, like R201C, activate the protein independently of GTP. A reciprocal mutation, R228C, disrupts GTP

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Signaling

Background:

  • Heterotrimeric G proteins are crucial signal transducers.
  • Mutations in Gαs, particularly R201C, are frequently linked to cancer.
  • The canonical model posits GTPase activity regulates Gαs function.

Purpose of the Study:

  • To investigate the mechanism of gain-of-function mutations in Gαs.
  • To explore how mutations affect GTP and GDP binding and activation.
  • To understand the molecular basis of Gαs-related diseases.

Main Methods:

  • Site-directed mutagenesis to create R201C and R228C mutations in Gαs.
  • Biochemical assays to measure GTPase activity and adenylyl cyclase activation.
  • Analysis of Gαs interaction with GTP and GDP analogs.

Main Results:

  • The R201C mutation activates GDP-bound Gαs by stabilizing an intramolecular hydrogen bond network, bypassing GTP binding.
  • The R228C mutation, associated with pseudohypoparathyroidism type 1a (PHP-Ia), impairs the adenylyl cyclase-activating function of GTP-bound Gαs.
  • These findings demonstrate that disease-associated mutations can alter the fundamental roles of GDP and GTP in Gαs regulation.

Conclusions:

  • Gαs mutations can subvert the canonical GDP/GTP switch mechanism.
  • Gain-of-function mutations can activate Gαs even in the GDP-bound state.
  • Loss-of-function mutations can interfere with GTP-mediated activation, offering new therapeutic targets.
Keywords:
G proteinGNASGTPaseGαsR201CR288Cadenylyl cyclasecancerpsuedohypoparathyroidism type 1a

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