Tyrosine phosphorylation switching of a G protein

Bo Li, Meral Tunc-Ozdemir, Daisuke Urano, Haiyan Jia, Emily G. Werth, David D. Mowrey, Leslie M. Hicks, Nikolay V. Dokholyan, Matthew P. Torres, Alan M. Jones

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Heterotrimeric G protein complexes are molecular switches relaying extracellular signals sensed by G protein-coupled receptors (GPCRs) to downstream targets in the cytoplasm, which effect cellular responses. In the plant heterotrimeric GTPase cycle, GTP hydrolysis, rather than nucleotide exchange, is the rate-limiting reaction and is accelerated by a receptor-like regulator of G signaling (RGS) protein. We hypothesized that post-translational modification of the G subunit in the G protein complex regulates the RGS-dependent GTPase cycle. Our structural analyses identified an invariant phosphorylated tyrosine residue (Tyr166 in the Arabidopsis G subunit AtGPA1) located in the intramolecular domain interface where nucleotide binding and hydrolysis occur. We also identified a receptor-like kinase that phosphorylates AtGPA1 in a Tyr166-dependent manner. Discrete molecular dynamics simulations predicted that phosphorylated Tyr166 forms a salt bridge in this interface and potentially affects the RGS protein-accelerated GTPase cycle. Using a Tyr166 phosphomimetic substitution, we found that the cognate RGS protein binds more tightly to the GDP-bound G substrate, consequently reducing its ability to accelerate GTPase activity. In conclusion, we propose that phosphorylation of Tyr166 in AtGPA1 changes the binding pattern with AtRGS1 and thereby attenuates the steady-state rate of the GTPase cycle. We coin this newly identified mechanism “substrate phosphoswitching.”.

Original languageEnglish (US)
Pages (from-to)4752-4766
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number13
DOIs
StatePublished - Mar 30 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Li, B., Tunc-Ozdemir, M., Urano, D., Jia, H., Werth, E. G., Mowrey, D. D., Hicks, L. M., Dokholyan, N. V., Torres, M. P., & Jones, A. M. (2018). Tyrosine phosphorylation switching of a G protein. Journal of Biological Chemistry, 293(13), 4752-4766. https://doi.org/10.1074/jbc.RA117.000163