Atypical activation of the G protein Gαq by the oncogenic mutation Q209P

Marcin Maziarz, Anthony Leyme, Arthur Marivin, Alex Luebbers, Prachi P. Patel, Zhe Chen, Stephen R. Sprang, Mikel Garcia-Marcos

Research output: Contribution to journalArticle

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Abstract

The causative role of G protein-coupled receptor (GPCR) pathway mutations in uveal melanoma (UM) has been well-established. Nearly allUMsbear an activating mutation in aGPCR pathway mediated by G proteins of the Gq/11 family, driving tumor initiation and possibly metastatic progression. Thus, targeting this pathway holds therapeutic promise for managing UM. However, direct targeting of oncogenic Gαq/11 mutants, present in α90% of UMs, is complicated by the belief that these mutants structurally resemble active Gαq/11 WT. This notion is solidly founded on previous studies characterizing Gα mutants in which a conserved catalytic glutamine (Gln-209 in Gαq) is replaced by leucine, which leads to GTPase function deficiency and constitutive activation. Whereas Q209L accounts for approximately half of GNAQ mutations in UM, Q209P is as frequent as Q209L and also promotes oncogenesis, but has not been characterized at the molecular level. Here, we characterized the biochemical and signaling properties ofGαq Q209P and found that it is also GTPase-deficient and activates downstream signaling as efficiently asGαq Q209L. However,Gαq Q209P had distinct molecular and functional features, including in the switch II region of Gαq Q209P, which adopted a conformation different from that of Gαq Q209L or active WT Gαq, resulting in altered binding to effectors, Gαα, and regulators of G-protein signaling (RGS) proteins. Our findings reveal that the molecular properties of Gαq Q209P are fundamentally different from those in other active Gαq proteins and could be leveraged as a specific vulnerability for the ∼20% of UMs bearing this mutation.

Original languageEnglish (US)
Pages (from-to)19586-19599
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number51
DOIs
StatePublished - Jan 1 2018

Fingerprint

Gq-G11 GTP-Binding Protein alpha Subunits
GTP Phosphohydrolases
Bearings (structural)
Chemical activation
RGS Proteins
Mutation
G-Protein-Coupled Receptors
Glutamine
Leucine
Conformations
Tumors
Switches
Carcinogenesis
Uveal melanoma
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Maziarz, M., Leyme, A., Marivin, A., Luebbers, A., Patel, P. P., Chen, Z., ... Garcia-Marcos, M. (2018). Atypical activation of the G protein Gαq by the oncogenic mutation Q209P. Journal of Biological Chemistry, 293(51), 19586-19599. https://doi.org/10.1074/jbc.RA118.005291

Atypical activation of the G protein Gαq by the oncogenic mutation Q209P. / Maziarz, Marcin; Leyme, Anthony; Marivin, Arthur; Luebbers, Alex; Patel, Prachi P.; Chen, Zhe; Sprang, Stephen R.; Garcia-Marcos, Mikel.

In: Journal of Biological Chemistry, Vol. 293, No. 51, 01.01.2018, p. 19586-19599.

Research output: Contribution to journalArticle

Maziarz, M, Leyme, A, Marivin, A, Luebbers, A, Patel, PP, Chen, Z, Sprang, SR & Garcia-Marcos, M 2018, 'Atypical activation of the G protein Gαq by the oncogenic mutation Q209P', Journal of Biological Chemistry, vol. 293, no. 51, pp. 19586-19599. https://doi.org/10.1074/jbc.RA118.005291
Maziarz, Marcin ; Leyme, Anthony ; Marivin, Arthur ; Luebbers, Alex ; Patel, Prachi P. ; Chen, Zhe ; Sprang, Stephen R. ; Garcia-Marcos, Mikel. / Atypical activation of the G protein Gαq by the oncogenic mutation Q209P. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 51. pp. 19586-19599.
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